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The molecular basis of human retinal and vitreoretinal diseases
Berger, W; Kloeckener-Gruissem, B; Neidhardt, J
Berger, W; Kloeckener-Gruissem, B; Neidhardt, J (2010). The molecular basis of human retinal and vitreoretinal
diseases. Progress in Retinal and Eye Research, 29(5):335-375.
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Originally published at:
Progress in Retinal and Eye Research 2010, 29(5):335-375.
The molecular basis of human retinal and vitreoretinal diseases
The molecular basis of human retinal and vitreoretinal diseases
Wolfgang Berger1,2,3,*, Barbara Kloeckener-Gruissem1,4 and John Neidhardt1
1
Division of Medical Molecular Genetics and Gene Diagnostics,
Institute of Medical Genetics, University of Zurich,
Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland
2
Neuroscience Center Zurich, Zurich, Switzerland
3
Zurich Center for Integrative Human Physiology, Zurich, Switzerland
4
Department of Biology, ETH Zurich, Zurich, Switzerland
*Corresponding author
Address:
Division of Medical Molecular Genetics and Gene Diagnostics
Institute of Medical Genetics
University of Zurich
Schorenstrasse 16
CH-8603 Schwerzenbach
Switzerland
Tel.: + 41 44 655 70 31
Fax: + 41 44 655 72 13
Email: [email protected]
http://www.medmolgen.uzh.ch
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The molecular basis of human retinal and vitreoretinal diseases
1.
Introduction
2.
Non-syndromic retinal and vitreoretinal diseases
2.1
Diseases of rod photoreceptor cells (stationary and progressive)
2.1.1 Stationary rod diseases / Congenital stationary night blindness (CSNB)
2.1.2 Retinitis pigmentosa (RP) / Progressive rod diseases
2.2
2.2.1
2.2.2
2.2.3
Cone and cone rod diseases (stationary and progressive)
Stationary cone dysfunctions / Color vision defects (CVD)
Cone and cone rod dystrophies (CODs and CORDs)
Macular degenerations (monogenic and age-related)
2.3
2.3.1
2.3.2
2.3.3
Generalized photoreceptor diseases
Leber congenital amaurosis (LCA)
Choroideremia
Gyrate atrophy of the choroid and retina
2.4
Vitreoretinopathies
2.4.1 Erosive vitreoretinopathies (ERVR)
2.4.2 Exudative vitreoretinopathies (EVR)
3.
Syndromic retinal and vitreoretinal diseases
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
Usher syndrome (USH)
Bardet Biedl syndrome (BBS)
Senior Loken syndrome (SLSN, NPHP)
Refsum syndrome (Batten disease)
Joubert syndrome (JBTS)
Alagille syndrome (ALGS)
Alström syndrome (ALMS)
Neuronal ceroid lipofuscinosis (NCL, CLN)
Primary ciliary dyskinesias (PCD)
Stickler syndrome (STL)
4.
Genetic testing and counselling
5.
Therapeutic approaches to retinal degenerations
6.
Conclusions and outlook
7.
References and Internet Resources
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The molecular basis of human retinal and vitreoretinal diseases
Abstract
During the last two to three decades, a large body of work has revealed the
molecular basis of many human disorders, including retinal and vitreoretinal
degenerations and dysfunctions. Although belonging to the group of orphan diseases,
they affect probably more than two million people worldwide. Most excitingly,
treatment of a particular form of congenital retinal degeneration is now possible. A
major advantage for treatment is the unique structure and accessibility of the eye and
its different components, including the vitreous and retina. Knowledge of the many
different eye diseases affecting retinal structure and function (night and color
blindness, retinitis pigmentosa, cone and cone rod dystrophies, photoreceptor
dysfunctions, as well as vitreoretinal traits) is critical for future therapeutic
development. We have attempted to present a comprehensive picture of these
disorders, including clinical, genetic and molecular information. The structural
organization of the review leads the reader through non-syndromic and syndromic
forms of (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized
retinal degenerations and (iv) vitreoretinal disorders, caused by mutations in more
than 165 genes. Clinical variability and genetic heterogeneity have an important
impact on genetic testing and counselling of affected families. As phenotypes do not
always correlate with the respective genotypes, it is of utmost importance that
clinicians, geneticists, counsellors, diagnostic laboratories and basic researchers
understand the relationships between phenotypic manifestations and specific genes,
as well as mutations and pathophysiologic mechanisms. We discuss future
perspectives.
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The molecular basis of human retinal and vitreoretinal diseases
1.
Introduction
Monogenic diseases of the retina and vitreous affect approximately 1 in 2000
individuals, or more than 2 million people worldwide. Consequences for affected
individuals are variable and can range from legal blindness in the most severe forms
of retinal degenerations (Leber congenital amaurosis, LCA) to less severe or rather
mild retinal dysfunctions (night blindness, achromatopsia). For most of them, no
treatment can be offered. In the past 20-25 years, the knowledge about the molecular
basis of retinal diseases has tremendously progressed and evidence for the
contribution of genetic factors but also environmental circumstances is continuously
accumulating. After a time period that was mainly characterized by the identification
of genes and disease causing mutations for the monogenic retinal and vitreoretinal
traits in families, we have now entered an era where not only monogenetic (classic
Mendelian) but also multifactorial diseases are in the interest of clinical, genetic and
basic research. Still, a reliable molecular diagnosis is possible for only half of the
affected individuals or families with monogenic forms of retinal diseases. In addition,
the predictive value of a mutation or risk allele for multifactorial disorders is
problematic since the phenotypic and/or symptomatic consequences are highly
variable. Nevertheless, the knowledge about the molecular mechanisms has also
improved diagnostic assessment of patients by genetic testing. It is the ultimate goal
to better understand the molecular etiology of these diseases and to develop
approaches for therapeutic interventions.
The diseases discussed in this article can be categorized in four major groups: (i) rod
dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal
degenerations (affecting both photoreceptor cell types, rods and cones), and finally
(iv) exudative as well as erosive vitreoretinopathies (Figure 1). Our disease
classification also considers whether the ocular phenotype is associated with
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The molecular basis of human retinal and vitreoretinal diseases
pathologies of other tissues (syndromic forms) or only affects the retina, retinal
pigment epithelium and the vireous body (non-syndromic forms). In addition, the
mode of inheritance was used as one characteristic feature of the different disease
phenotypes in order to categorize them. Our aim was to provide a comprehensive
overview about the molecular basis of retinal and vitreoretinal diseases and to
discuss selected aspects in more detail.
2.
Non-syndromic retinal and vitreoretinal diseases
2.1
Diseases of rod photoreceptor cells (stationary and progressive)
Rod photoreceptors represent the vast majority of light sensitive cells in the human
retina. There are approximately 20 times more rods than cones. These cells are
spezialized for low light intensities and are responsible for visual perception under
dim light conditions. The center of the human retina, which contains the macula and
fovea centralis, is devoid of rod photoreceptor cells but the flanking areas have the
highest rod content, which decreases almost lineary towards the retinal periphery.
The two major classes of stationary and progressive retinal diseases in humans are
represented by different forms of stationary night blindness and retinitis pigmentosa,
respectively.
2.1.1 Congenital stationary night blindness / stationary rod diseases
As the name implies, congenital stationary night blindness (CSNB) is a nonprogressive visual impairment present at birth. However, it is also one of the first
symptoms in progressive diseases, including retinitis pigmentosa (RP). Therefore, a
differential diagnosis by genetic testing can provide helpful and important information
to the affected individuals and families, in order to exclude or confirm the clinical
diagnosis and to provide counselling.
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CSNB is heterogeneous in clinical and genetic terms. Currently, 11 genes are known
to carry sequence alterations or mutations, which are associated with this disease
(Figure 2, Table 1) (Audo et al., 2009; Bech-Hansen et al., 1998; Bech-Hansen et al.,
2000; Dryja et al., 1993; Dryja et al., 1996; Dryja et al., 2005; Fuchs et al., 1995; Gal
et al., 1994; Li et al., 2009; Pusch et al., 2000; Strom et al., 1998; van Genderen et
al., 2009; Wycisk et al., 2006; Yamamoto et al., 1997; Zeitz et al., 2005; Zeitz et al.,
2006). Mutations in these genes can be dominant, recessive or X-linked. With
respect to clinical manifestations, several forms can be distinguished: Schubert
Bornschein type of CSNB, the complete and the incomplete type of CSNB, and
CSNB with fundus abnormalities. One of the most important diagnostic tools to
discriminate the different clinical types is the electroretinogram (ERG), which
measures the response of different retinal cell types to light. Schubert Bornschein
CSNB shows a negative scotopic (dim light conditions) ERG, with normal a-wave
(photoreceptor response) amplitude that is larger than that of the b-wave (bipolar cell
and second order neuron response). Also, dark adaptation of rods is reduced
drastically or even completely absent, while cone adaptation thresholds are variably
elevated in most patients. There are two types of CSNB with regard to ERG
characteristics: (i) the Riggs type with an absent rod and reduced cone response in
the ERG and (ii) the Schubert Bornschein type with a so-called negative ERG under
scotopic conditions. The Nougaret type of CSNB, which has been described in a
large French family, is characterized by the Riggs type ERG and autosomal dominant
inheritance. The disease was found to be due to mutations in the alpha subunit of
transducin (Dryja et al., 1996). The Schubert Bornschein disease can be subdivided
in (i) CSNB1 or complete CSNB and (ii) CSNB2 or incomplete CSNB. In CSNB1, the
rod b-wave is significantly reduced or absent, while that of the cones is largely
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The molecular basis of human retinal and vitreoretinal diseases
normal. In the incomplete type of CSNB, both the rod and the cone b-wave
amplitudes are reduced (Zeitz, 2007).
The functional spectrum of genes involved in CSNB contains calcium channel
subunits (CACNA1F, CACNA2D4, TRPM1), a calcium binding protein (CABP4), a
metabotropic glutamate receptor (GRM6), but also molecules of the
phototransduction cascade (GNAT1, GRK1, PDE6B, SAG, RHO) as well as proteins
of unknown function (NYX). Interestingly, mutations in Rhodopsin and the beta
subunit of the rod phosphodieasterase can lead to stationary and progressive retinal
diseases. While most of the mutations in the RHO gene lead to autosomal dominant
or recessive RP (see below), a few amino acid substitutions have been described
which lead to stationary night blindness (Figures 2 and 6) (al Jandal et al., 1999;
Dryja et al., 1993; Rao et al., 1994; Sieving et al., 1995; Sieving et al., 2001; Zeitz et
al., 2008). The respective mutations may lead to a constitutively active signal
transduction at a relatively low level, which makes affected rod photoreceptor cells
less sensitive to low light intensities. This has been shown for rhodopsin mutations
(Sieving et al., 2001; Zeitz et al., 2008). The missense mutation c.884C>T
(p.Ala295Val) in rhodopsin was found in a Swiss family with autosomal dominant
CSNB. It was characterized in a functional assay, where the catalytic GTP exchange
of transducin was measured. In the presence of 11-cis retinal, the respective mutant
rhodopsin was found to be inactive, similar to wild-type. Contrary, in the absence of
11-cis-retinal, unlike wild-type opsin, the mutant opsin constitutively activated
transducin (Zeitz et al., 2008). Because of this constitutive activity, the affected
individuals experience decreased sensitivity to light.
In addition to this defect in rod photoreceptor cells themself, signal transmission
between photoreceptors and the respective bipolar cells may be disturbed or even
eliminated by mutations in different genes. The calcium channel subunits or the
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metabotropic glutamate receptor mGluR6/GRM6 are interesting molecules to study
and for understanding the complex interactions between photoreceptor and bipolar
cells (Dryja et al., 2005; Zeitz et al., 2005).
2.1.2 Retinitis pigmentosa and progressive rod cone diseases
The term retinitis pigmentosa (RP) describes a group of clinically similar phenotypes
associated with genetically heterogeneous causes. The disease onset and
progression may vary significantly among patients, even within the same family. The
patients frequently experience night blindness in the early phase of the disease,
followed by loss of vision starting in the midperiphery and progressing towards the
center which results in tunnel vision (Hamel, 2006). On the cellular level, these
phenotypes correlate with a predominantly affected rod photoreceptor system. In
later stages, the disease may further affect the cone photoreceptors eventually
causing complete blindness. The diseased photoreceptors undergo apoptosis which
is reflected in reduced outer nuclear layer thickness within the retina, as well as in
lesions and/or retinal pigment deposits in the fundus. Patients may loose a significant
portion of their photoreceptors before experiencing loss of visual acuity (Geller et al.,
1993). To assess the disease status and progression, electroretinographic
measurements provide a sensitive method (Berson, 1993). In contrast to CSNB,
which predominantly affects the b-wave, RP is characterized by reduced or absent aand b-waves in the ERG.
The prevalence of RP is estimated to be about one in 3500 individuals (Hartong et al.,
2006). After the first report about linkage of an RP locus to a DNA marker on human
chromosome X twenty six years ago (Bhattacharya et al., 1984), over 40 genes have
been associated with RP (Figure 2, Table 2). Disease causing mutations may be
inherited autosomal recessive (Abd El-Aziz et al., 2008; Banerjee et al., 1998; Bareil
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The molecular basis of human retinal and vitreoretinal diseases
et al., 2001; Collin et al., 2008; den Hollander et al., 1999; Dryja et al., 1995; Gal et
al., 2000; Huang et al., 1995; Martinez-Mir et al., 1998; Maw et al., 1997; Maw et al.,
2000; McLaughlin et al., 1993; Morimura et al., 1998; Nakazawa et al., 1998; Rivolta
et al., 2000; Thompson et al., 2001; Tuson et al., 2004; Zangerl et al., 2006; Zhang et
al., 2007b) or dominant (Abid et al., 2006; Bowne et al., 2002; Chakarova et al., 2002;
Chakarova et al., 2007; Farrar et al., 1991; Freund et al., 1997; Friedman et al., 2009;
Kajiwara et al., 1991; Kajiwara et al., 1994; Keen et al., 2002; Kennan et al., 2002;
McKie et al., 2001; Rebello et al., 2004; Sato et al., 2005; Vithana et al., 2001; Wada
et al., 2001; Zhang et al., 2007a; Zhao et al., 2009), as well as X-linked (Meindl et al.,
1996; Roepman et al., 1996a; Roepman et al., 1996b; Schwahn et al., 1998).
Interestingly, mutations in several genes can be either dominant or recessive (Bernal
et al., 2008; Bessant et al., 1999; Coppieters et al., 2007; Davidson et al., 2009;
Dryja et al., 1990; Morimura et al., 1999; Pierce et al., 1999; Sullivan et al., 1999).
The majority of cases (50-60%) are autosomal recessive, sporadic or simplex
(Hartong et al., 2006). Also, families with autosomal dominant (30-40%) and X-linked
inheritance (5-20%) are frequently observed. Maternal (mitochondrial) inheritance is
very rare in RP.
The functions of the different RP-associated genes may be grouped into mainly five
categories: (i) phototransduction, (ii) retinal metabolism, (iii) tissue development and
maintenance, (iv) cellular structure, and (v) splicing.
The splicing category will now be discussed in more detail. It is particularly interesting
as it only contains genes that are widely expressed although the patients’ phenotype
is restricted to photoreceptors in the retina. Around 10% of the RP-associated genes
belong to this rather recently discovered category. The splicing-relevant gene
products (PRPF3, PRPF8, PRPF31 and PAP1) are involved in the assembly of the
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spliceosome, a basic component of the splicing machinery. The spliceosomal protein
complex catalyzes the removal of intronic sequences from pre-mRNA transcripts.
Since the removal of introns is essential for almost all transcripts of the cell, it is
intriguing that mutations in genes of the splicing category exclusively result in RP.
Possible explanations for this observation are: (1) Photoreceptors have specialized
splicing machineries that make them more vulnerable to alterations in splice
components than other cell types. (2) The splicing of photoreceptor-specific genes is
selectively affected. (3) Due to specialized requirements (e.g. transcript turnover),
photoreceptors depend more strongly than other cell types on efficient splicing.
Studies first supported possible explanation 2 and suggested that the removal of
intron 3 of RHO is inhibited by the mutated splice factor PRPF31 (Yuan et al., 2005).
The authors expressed the mutated PRPF31 to detect the splice defect in RHO.
Subsequently, studies suggested that haploinsufficiency is the underlying mechanism
for PRPF31 mutations, i.e. the mutated allele is not expressed and the reduced gene
dosage causes the disease (support for possible explanation 3) (Rio et al., 2008).
Nevertheless, splicing of RPGR intron 9 has been found to be misregulated in
patient-derived lymphoblastoid cell lines with PRPF31 mutations. In contrast, cell
lines with PRPF8 mutations show more general splice defect of several transcripts
(Ivings et al., 2008). The latter findings suggest that different disease mechanisms
underly RP caused by mutations in different splice factor genes.
Although the functional properties of several RP-associated genes have been
extensively studied, genotype-phenotype correlations are incompletely understood.
Frequently, they are complicated by multiple clinical features caused by mutations in
the same gene (Figure 6). This observation often involves the complex molecular
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The molecular basis of human retinal and vitreoretinal diseases
properties of a single RP gene. Subsequently, examples will be discussed to
illustrate the problems associated with genotype-phenotype correlations.
RHO is among the most prominent RP-associated genes. RHO constitutes a 7transmembrane receptor protein which initiates the phototransduction cascade upon
absorption of light by its chromophore 11-cis-retinal. The vast majority of mutations
show a classical autosomal dominant inheritance leading to RP, the mechanism of
which is fairly well understood as being either a gain-of-function or a dominant
negative effect of the mutated protein (Mendes et al., 2005). Nevertheless, few
mutations show an autosomal recessive inheritance or lead to night blindness only.
Convincing models exist for RHO mutations associated with night blindness and
have been discussed above. It is less clear why the missense mutation p.E150K in
RHO was found to cause RP only in a homozygous state, whereas heterozygous
carriers developed no RP phenotype. This is indicative of a recessive inheritance
pattern (Kumaramanickavel et al., 1994). It is well possible that these recessive RHO
mutations constitute exceptionally mild mutations that are either tolerated by the
photoreceptor or lead to RP late in live (Neidhardt et al., 2006). The same may apply
to night blindness-associated mutations.
Overall, the progression of clinical symptoms in patients with RHO mutations seems
milder compared to that in patients with RPGR mutations (Sandberg et al., 2007).
The reason for this clinical variability is not understood. RPGR is the major X-linked
recessive RP gene and is frequently associated with mutations in male patients. Male
to male transmission of the phenotype does not occur. Nevertheless, families with
dominant inheritance pattern, as well as patients showing other forms of retinal
degenerations have been reported (Figures 2, 3 and 6) (Ayyagari et al., 2002;
Demirci et al., 2002; Neidhardt et al., 2008). Also, there are a few examples of female
carriers showing disease symptoms of variable degree (Banin et al., 2007; Li et al.,
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The molecular basis of human retinal and vitreoretinal diseases
2005; Rozet et al., 2002). This effect might be attributed to a dominant nature of
some of the mutations or non-random X-inactivation in the affected tissue, which has
not been proven so far. An interesting feature of the RPGR gene is the generation of
large numbers of splice variants (Kirschner et al., 1999; Kirschner et al., 2001). The
alternative exon ORF15 of RPGR is expressed predominantly in retina and is a hotspot for RP-associated mutations (Vervoort et al., 2000). ORF15 transcripts give rise
to several splice variants (Hong et al., 2002). Nevertheless, mutations in ORF15 are
almost exclusively frameshift or stop mutations that cause premature termination
codons. Thus this exon is likely to play a crucial role for the function of RPGR in the
retina. Interestingly, mutations at the 3’ end of exon ORF15 tend to result
predominantly in cone over rod dystrophies rather than RP (Ayyagari et al., 2002;
Demirci et al., 2002; Moore et al., 2006; Ruddle et al., 2009; Shu et al., 2007; Walia
et al., 2008; Yang et al., 2002). This indicates that functional properties of the 3’- or
C-terminal RPGR region are relevant for the survival of cones. Furthermore, the
existence of alternative splice variants affecting this part of the gene complicates a
clear genotype-phenotype correlation, but indicates that transcript processing is
involved in the underlying pathogenic process. We provided further support for the
observation that RPGR splice variants are relevant for the function of cones and
showed that RPGR isoforms containing the alternative exon 9a are predominantly
expressed in cones of the human retina (Neidhardt et al., 2007). Since splicing is
tightly regulated and its mis-regulation has previously been associated with several
diseases (Faustino et al., 2003), even mild alterations of the patients’ splice pattern
might give rise to modifications of the phenotype (Schmid et al., 2010). Consequently,
up or down regulation of tissue-specific RPGR isoforms might be responsible for a
shift between different clinical expressions like RP and COD and might further
influence the phenotype in heterozygous mutation carriers.
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Also in mice, the phenotype is variable and depends on the genetic background. We
have generated mutant mouse lines with an in-frame deletion of exon 4 of the Rpgr
gene (Brunner et al., 2009). This mutation was introduced in two different inbred
mouse lines: either C57BL/6 or BALB/c. On the BL/6 background, the phenotype is
rod dominated while it is predominantly affecting cones in the BALB/c line.
Furthermore, mislocalization of rhodopsin and cone opsin is consistent with a
function of Rpgr in transport mechanisms, as reported previously (Khanna et al.,
2005; Roepman et al., 2000). This functional property of Rpgr is also supported by
our findings in transgenic mice with overexpression of the protein. We observed that
male infertility was due to aberrant spermatozoa (Brunner et al., 2008). The
associated flagellar phenotype was more severe in mice with a high copy number of
the transgene compared to mice carrying less Rpgr copies. These findings further
support a role of Rpgr in ciliary transport and show that it is not confined to the retina.
This also explains why RPGR mutations in patients can lead to a syndromic
phenotype.
2.2
Cone and cone rod diseases (stationary and progressive)
As mentioned above, the cone photoreceptor cells in the human retina are
responsible for daylight vision and are instrumental for high visual acuity and colour
discrimination. A recent review about the structure and evolution of the cone system
summarizes our current knowledge about this class of photoreceptor cells (Mustafi et
al., 2009). Only 5% of photoreceptor cells are cones. A human retina contains
approximately 60 million rods and 3 million cones. The cone system has a high
spatial resolution but is less sensitive to light as compared to rods. During evolution,
primates have acquired trichromatic colour vision. Other mammals, including mice,
are dichromatic. The three cone types (red, green and blue) in humans are
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designated L, M, and S cones according to their sensitivity to photons. The L cones
are most sensitive to low frequency photons (555-565 nm), the M cones to middle
frequency photons (530-537 nm), and the S cones to supra frequency photons (415430 nm). There are twice as many L than M cones and the S cones constitute only
5% of all cone photoreceptors.
The cone photoreceptor cells are not evenly distributed in primate retinas. The
macular region and its centre, the fovea centralis, contain almost exclusively cones,
except S cones, which are located more peripherally. The gene NRL, which codes for
a transcription factor, plays a crucial role during photoreceptor differentiation and
promotes the rod development while it suppresses the cone programme.
Human diseases that affect the cone system, such as macular or cone and cone rod
degenerations, lead to severe visual impairment. Clinically, patients with these
diseases have a decreased visual acuity, photophobia, nystagmus, and colour vision
abnormalities. Night blindness occurs in later stages of the disease when the rod
system also becomes affected. However, cone diseases can be stationary, e.g. the
different forms of complete and incomplete achromatopsia.
2.2.1 Stationary cone dysfunctions
Stationary subtypes of cone dysfunctions are complete and incomplete
achromatopsia. They are usually congenital. Affected individuals with complete
achromatopsia show infantile nystagmus, poor visual acuity, photophobia and are
unable to distinguish colours. Mutations in four genes can cause complete
achromatopsia: CNGA3, CNGB3, GNAT2 and PDE6C (Figure 3, Table 1) (Chang et
al., 2009; Kohl et al., 1998; Kohl et al., 2000; Kohl et al., 2002; Thiadens et al., 2009;
Wissinger et al., 2001). GNAT2 codes for the cone-specific form of transducin, an
essential component of the phototransduction cascade. CNGA3 and CNGB3 code
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for the alpha 3 and beta 3 subunits of the cyclic nucleotide gated chanel and are
responsible for the ultimate step of the phototransduction cascade in cone
photoreceptors that leads to membrane hyperpolarization when the channel is closed.
PDE6C codes for the cone-specific alpha subunit of the cGMP phosphodiesterase. It
plays a key role in the essential phototransduction cascade of cone photoreceptors
and mutations were recently found in cone dysfunction diseases (Thiadens et al.,
2009).
Patients with incomplete or atypical achromatopsia retain residual colour vision. Their
visual acuity is mildly better compared to that of individuals with the complete form of
the disease. All other symptoms are identical in both forms of the disease. Mutations
in three autosomal genes (CNGA3, GNAT2 and PDE6C) have been associated with
incomplete achromatopsia (Figure 3, Table 1). While the affore mentioned diseases
affect all three cone types, there is one X-linked recessive stationary disease that
affects the red and green opsin genes and consequently only two types of cones.
The disease is designated blue cone monochromatism. This X-linked form of
incomplete achromatopsia is associated with reduced visual acuity, nystagmus, and
photophobia. The underlying gene defect involves the green (M) and the red (L)
opsin genes on the human X chromosome (Nathans et al., 1986). Two disease
mechanisms were proposed, which lead to a lack of functional opsin molecules:
Either a loss of transcription caused by a deletion of the locus control region (LCR)
upstream of the genes or the presence of a hybrid gene due to an unequal crossing
over of the highly homologous red and green opsin genes. The latter reduces the
number of tandemly arrayed opsin genes on the X chromosome to a single hybrid
gene.
Another stationary cone disease, designated oligocone trichromacy, presents with
reduced visual acuity, mild photophobia, a reduced amplitude in the cone ERG but
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The molecular basis of human retinal and vitreoretinal diseases
normal colour vision (Andersen et al., 2009; Michaelides et al., 2004). A reduced
number of foveal cones may be responsible for this disease. So far, mutations in the
genes encoding the cone-specific transducin alpha subunit (GNAT2) and the beta 3
subunit of the cyclic nucleotide gated channel (CNGB3) were associated with this
form of cone dysfunction (Andersen et al., 2009; Rosenberg et al., 2004).
2.2.2 Cone and cone rod dystrophies (CODs and CORDs)
The age of onset for CODs or CORDs is usually during childhood or early adult life.
The progressive cone diseases are generally more severe than the progressive rod
dominated phenotypes (e.g. RP). Although some peripheral vision is preserved, it
can lead to legal blindness earlier than RP. Affected individuals experience first
symptoms of decreased visual acuity at school during the first decade of life. In
addition, patients with progressive CODs and CORDs feel intense photophobia and
variable degrees of colour vision abnormalities. Central scotomas can be also
present upon visual field testing. The fundus examination frequently reveals pigment
deposits and retinal atrophy in the macular region. To discriminate CORDs from
CODs and macular degeneration, additional ophthalmologic examinations are
needed (fluorescein angiography, fundus autofluorescence, ERG). In contrast to
CODs, CORDs show a peripheral retinal involvement and the ERG is characterized
by a decrease in both cone and rod responses. However, cone responses are more
severely affected than the rod-specific ERG components. In pure CODs or early
CORDs, scotopic ERG is normal. In later disease stages, night blindness occurs and
the loss of the peripheral visual field is progressing. This is different in rod dominated
retinal diseases, where night blindness is one of the first symptoms and the disease
progresses from the periphery to the centre.
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Currently, about 20 different genes have been shown to carry mutations that cause
non-syndromic progressive cone disease (Figure 3, Table 3). The mode of
inheritance is either autosomal dominant, recessive, or X-linked.
2.2.3
Macular degenerations (monogenic and AMD)
The macula, a region of the retina with high density of cone photoreceptors, can
undergo specific degenerative processes, called macular degeneration. In this
review, we discuss the classic monogenic forms of macular degeneration but also the
multifactorial, age-related form of this disease.
The heterogeneous clinical features of macular dystrophies include a progressive
loss of visual acuity, colour vision abnormalities, and central scotomas. The disease
can manifest early or late in life. The typical and very frequent age-related form of
macular dystrophy is not a classic monogenic disease but involves a complex
interaction of multiple genetic components and environmental factors.
Patients with macular degenerations usually show a normal or only slightly reduced
electrophysiologic response upon ERG and EOG testing. This is different to more
generalized or severe cone as well as rod dominated diseases, which show a
significant reduction of the a-wave amplitude in the scotopic ERG and can be used
as a characteristic feature for differential diagnosis. Full field ERG is often normal,
even if the patients are legally blind due to a macular degeneration. Application of a
more sensitive method, multifocal ERG, allows measurements by recording
electrophysiologic responses from hundreds of small retinal areas simultaneously
within less than 10 minutes per eye (Marmor et al., 2003). With this method,
scotomas of only a few millimeters in diameter can be identified and accurate
quantification of the extent of retinal dysfunction is possible.
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2.2.3.1
Monogenic macular dystrophies
Monogenic macular dystrophies can occur as a part of a multiorgan disease (e.g.
Alport syndrome, BBS, Refsum disease) or in non syndromic forms. The mode of
inheritance can be dominant, recessive, or X-linked. However, most of the mutations
show a dominant effect. Currently, more than 10 genes have been identified which
carry pathogenic sequence variants in patients with macular degenerations (Figure 3,
Table 4a).
Mutations in the ABCA4 gene, which encodes an ATP-binding cassette transporter,
can lead to a variety of retinal degenerative diseases, including juvenile macular
degeneration (Stargardt disease), RP, as well as cone or cone rod dystrophy
(Allikmets et al., 1997; Briggs et al., 2001; Cremers et al., 1998; Fishman et al., 2003;
Kitiratschky et al., 2008; Maugeri et al., 2000; Rozet et al., 1998). The combination of
these different clinical entities has been observed even within a family (Klevering et
al., 2004a). This might be due to the high frequency of ABCA4 mutation carriers in
the general population (about 5%) (Maugeri et al., 1999). The ABCA4 gene encodes
a membrane protein of the rod and cone photoreceptor outer segment disks (Sun et
al., 1997). The gene consists of 50 exons and the open reading frame contains 2273
amino acid residues. ABCA4 mutations may show variable expressivity of the
phenotype. They can lead to COD, CORD, MD, or RP (Figures 2, 3 and 6, Tables 2,
3, 4a and 4b).
The variable expressivity of mutations in a single gene is also observed for peripherin
(PRPH2) (Figures 2, 3 and 6, Tables 2, 3 and 4a). In the vast majority of cases,
mutations are dominant and can lead to RP, pattern dystrophy, fundus flavimaculatus,
vitelliform macular dystrophy, or cone rod dystrophy (Felbor et al., 1997; Kajiwara et
al., 1991; Keen et al., 1994; Nakazawa et al., 1994; Weleber et al., 1993). PRPH2
mutations were also shown to be responsible for digenic RP (Kajiwara et al., 1994).
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This form of RP is caused by mutations in ROM1 and PRPH2 and only double
heterozygotes develop disease symptoms. Variability of clinical manifestations of
PRPH2 mutations was also observed within the same family (Apfelstedt-Sylla et al.,
1995).
2.2.3.2
Age-related macular degeneration (AMD)
As the name indicates, this form typically affects the elder population. Not only age
but also hypertension, smoking, diet, obesity and chronic inflammation have been
discussed as environmental risk factors (Ambati et al., 2003). Based on twin and
family studies, convincing data have been collected that show a substantial
contribution from genetic constitutions of the individual (reviewed by (Chamberlain et
al., 2006; Patel et al., 2008)).
AMD has a prevalence of 0.05% before the age of 50 years, which increases to
about 12 % in a population older than 80 years of age. With a general tendency of an
aging population, this condition of vision loss will cause an increasing amount of
individual discomfort and associated costs (Augood et al., 2006; Javitt et al., 2003;
Klaver et al., 2001). Ethnic barriers to attract the disease have not been described
but differences in the severity of the clinical appearance are recognized.
Several reviews provide different aspects of the progression in the field of AMD
(Chamberlain et al., 2006; Edwards et al., 2007; Haddad et al., 2006; Lotery et al.,
2007; Patel et al., 2008; Scholl et al., 2007; Swaroop et al., 2007; Tuo et al., 2004).
We would like to discuss here the genetic heterogeneity and its impact on the
complexity of AMD. The etiology of AMD differs from that of the monogenic forms of
macular degenerations, which is also reflected by the fact that a combination of
multiple genetic loci (Table 4b) but also environmental circumstances are responsible
for the development of AMD (Patel et al., 2008; Scholl et al., 2007). In the age19
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related form one can observe abnormalities of the retinal pigment epithelium (RPE)
as well as the formation of characteristic deposits containing lipids and proteins,
designated drusen. In general, two different types of AMD can be distinguished: (i) an
exudative or wet form of AMD and (ii) a non-exudative or dry form. The latter can
transform to an exudative form, which is found in about 15% of all patients. In this
form of AMD choroidal neovascularization (CNV) develops, which tends to cause
vessel leakage and consequently bleeding occurs. The drusen can vary greatly in
their position, number and size. This phenotypic variability has contributed to the
difficulties of recognizing a straight phenotype-genotype correlation.
To identify genetic determinants involved in complex diseases, several approaches
have been taken. The candidate gene approach has focused primarily on three
aspects: (i) genes which had previously been identified in monogenic macular
degenerations ; (ii) candidate genes which were chosen based on their function and
(iii) genes within regions identified through linkage studies (Chamberlain et al., 2006;
Patel et al., 2008; Scholl et al., 2007). Due to limited access to large families and the
uncertainty of a genetic model, association studies became more promising than
linkage analyses, in particular with the availability of increased numbers of genetic
markers (single nucleotide polymorphisms, SNPs) and therefore increased power of
analysis, despite a small sample size. In this review, we will focus on the
understanding we have gained from studying candidate genes that can predispose to
AMD.
The role of the immune system in AMD
The complement system is part of the innate defense mechanism. A large number of
proteins (about 30) participate in a cascade reaction of which three different
pathways have been described: the classical, the alternative and the lectin pathway.
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The cascade can be inhibited by the complement factor H (CFH), a component of the
alternative pathway. Uncontrolled activation of the system may lead to the formation
of drusen (Sivaprasad et al., 2006). Histological analysis of the retina of AMD
patients allowed the detection of many components of the complement system within
these structures (Hageman et al., 2001). Assessment of the frequency of the
p.Y402H variant, (c.1277T> C) (SNP rs1061170) of CFH in AMD patients compared
to control populations allowed the identification of the first risk locus (odds ratios
ranging between 4.54 and 11.61 in homozygous individuals) (Edwards et al., 2005;
Haines et al., 2005; Klein et al., 2005; Zareparsi et al., 2005). Individuals that carry
the histidine variant at position 402 of the protein are at approximately 50% risk to
develop AMD, either the form of geographic atrophy or the exudative, neovascular
form (Patel et al., 2008). Accordingly, non-carriers may experience protection against
AMD. Environmental risks, such as smoking and body mass index, do not appear to
increase the risk in combination with the CFH sequence variants (Lotery et al., 2007).
In contrast, ethnic origin was reported to have a modifying effect (Lotery et al., 2007).
Since amino acid position 402 lies within a region of CFH that interacts with heparin
and C-reactive protein (CRP) (Giannakis et al., 2003) it was suggested that altered
binding to these components on the outer retinal surface could affect the level of
inflammation and consequently affect the development of AMD (Edwards et al., 2005;
Haines et al., 2005; Klein et al., 2005). Spurred by this initial report, several other
studies confirmed the association of CFH with AMD. A meta-analysis indicated a
multiplicative genetic model with each risk allele increasing the odds of AMD by
approximately 2.5 fold (Thakkinstian et al., 2006).
While the CFH p.Y402H variant is associated with AMD in Caucasian (Conley et al.,
2005; Hageman et al., 2005; Kim et al., 2008; Maller et al., 2006; Narayanan et al.,
2007; Scholl et al., 2008; Seddon et al., 2009; Zareparsi et al., 2005) and Chinese
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populations (Lau et al., 2006), it was not found in Japanese patients with exudative
AMD (Gotoh et al., 2006). Several factors may explain population differences: first,
different allele frequencies (the C allele frequency is 0.282 in Caucasian population
(HAP-MAP CEU) and 0.057 in Japanese population (HAP-MAP JPT); Ref: NCBI May
2008); second, the prevalence of late stage AMD is higher in Caucasians compared
to Japanese population (Oshima et al., 2001) and third, formation of drusen is less
frequent in Japanese patients (Bird, 2003). Interestingly, the C allele is significantly
associated with the risk for AMD (odds ratio of 4.4) in the Han-Chinese (Beijing)
population, despite its only slightly higher frequency (frequency: 0.067) (Lau et al.,
2006). Whether the C-allele is associated with both forms of advanced AMD in the
Chinese population is not yet clear since only the neovascular form of AMD was
tested.
Complement factors CFB, C2 , C3 and C5 are further components involved in the
activation of the alternative pathway. CFB and C3 products were shown to
accumulate in drusen and Bruch’s membrane of AMD patients and genetic variants
for CFB and C2 confer increased risk (Odds ratio of 1.32) as well as protection (Odds
ratio 0.36 and 0.45) (Gold et al., 2006). These data have been confirmed in a
replication study (Spencer et al., 2007). By conferring reduced hemolytic activity, the
p.R32Q variant of CFB could contribute to the protective function (Gold et al., 2006;
Spencer et al., 2007). Furthermore, the absence of CFH-related genes CFHR1 and
CFHR3 is also associated with protection against AMD (Hughes et al., 2006). While
no association was found with variants in the C5 locus, the non-synonymous change
p.R102G in C3 was associated with both, the dry and wet form of AMD ( GR/RR:
odds ratio 1.61; GG/RR odds ratio 3.26) (Maller et al., 2007). This association was
independently confirmed in another Caucasian population (Spencer et al., 2008).
The possibility of interaction between the C3, CHF, CFB and C2 components could
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not be confirmed (Maller et al., 2007). Since complement C1 activates components
C2 and C4, inhibition of C1 leads to alteration of the complement cascade. DNA
sequence variants in the SERPING1 gene, which codes for the serine protease
family member serpin peptidase inhibitor, clad G, confer a protective effect on AMD,
regardless whether patients are affected by choroidal neovascularization (CNV) or
geographic atrophy (GA) (Ennis et al., 2008). Failure to replicate these findings in a
different patient cohort (Park et al., 2009) may reflect a cohort-specific effect.
Taken together, convincing evidence has been presented over the last four years
showing that sequence alterations in components of the complement cascade
contribute significant effects on the risk to develop AMD. Sequence variants in some
of them might provide protection against AMD development.
Perturbation of the signaling cascade leading to inflammation has also been
proposed to cause susceptibility to AMD (Ambati et al., 2003; Donoso et al., 2006).
Within this context, the G allele (c.1063A>G) of the toll-like receptor 4 (TRL4), a
bacterial endotoxin receptor, increases the risk of developing either the dry or wet
form of AMD within a Causasian population (odds ratio around 2.65) (Zareparsi et al.,
2005). In addition, TRL4 participates in the phagocytosis of photoreceptors, a
process which is important during the normal visual cycle and if perturbed, may lead
to AMD. Another Toll-like receptor gene, TRL3, which encodes a viral sensor that
supports the innate immune defense system could be associated with protective
function of a coding variant in AMD with geographic atrophy (odds ratio for the T
allele at SNP rs3775291 ranged between 0.198 and 0.712) but not with the
neovascular or early form (Yang et al., 2008b). Whether double stranded viral RNA,
the substrate for TRL3, does in fact exist in the eye, remains to be investigated. In
general, Yang and colleagues propose that this protective effect may be due to
suppression of RPE cell death. In an earlier study Edwards and colleagues reported
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only marginal association of variants in TRL3, TRL4 and TRL7 with AMD (Edwards et
al., 2008). It is noteworthy, that the number of patients with geographic atrophy was
relatively small (16% of 396 AMD patients) and may have diluted the association
results for the dry form of AMD.
The role of the stress response in AMD
A link between the immune response contributing to AMD and oxidative stress
damage was proposed from studies in mice (Hollyfield et al., 2008). It was
hypothesized that Increased oxidative stress may lead to an increase in modified
low-density lipoprotein, which in turn can be inhibited by paraoxonase (Mackness et
al., 1993). This enzyme is encoded by the gene PON1, of which two variants in the
protein coding sequence of the gene were shown to be associated with AMD in a
Japanese population (Chi square: 6.226 and 6.863 with P=0.445 and 0.323, for the
two variants respectively) (Ikeda et al., 2001). The attempt to replicate these findings
in a patient cohort from Australia failed (Baird et al., 2004). Different allele
frequencies together with differences in the AMD phenotype between these
populations might be the reason (Bird, 2003; Oshima et al., 2001).
Another stress response protein, serine pronase encoded by the HTRA1 gene on
chromosome 10q26, is expressed in the retina and the RPE and found at elevated
levels in drusen (Yang et al., 2006). HTRA1 is involved in the regulation of
degradation of extracellular matrix proteoglycans and binds to transforming growth
factor beta, which in turn regulates extracellular matrix deposition and angiogenesis
(Oka et al., 2004). Lotery and Trump speculated that overexpression may alter the
integrity of Bruch’s membrane, allowing the invasion of vasculature (Lotery et al.,
2007). These features and its location to a previously mapped risk region on
chromosome 10 made HTRA1 a candidate for conferring an effect on the likelihood
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to develop AMD, and in fact sequence variant rs11200638 in the promoter of HTRA1
confers a risk for AMD in Caucasian and Chinese populations. The SNP rs10490924
in the nearby ARMS2 (LOC387715) locus is also associated with an increased risk
for AMD. Since the two loci are in tight linkage disequilibrium it is difficult to
determine the relative contribution for each variant (odds ratios range between 2.7
and 11.14) (Dewan et al., 2006; Jakobsdottir et al., 2005; Rivera et al., 2005; Weger
et al., 2007; Yang et al., 2006). Recently, an insertion/deletion polymorphism near
the 3’end of the ARMS2(LOC387715) locus was found to affect polyadenylation of its
transcript (Fritsche et al., 2008). ARMS2 encodes a mitochondrial protein that
localizes to the ellipsoid region of the photoreceptors and may as such confer risk to
develop AMD (Fritsche et al., 2008). Furthermore, microsomal glutathione-Stransferase 1 (MGST-1) is part of the oxidative stress pathways and was implicated
to play a role in AMD (Maeda et al., 2005) but no association with AMD was found
(Haines et al., 2006).
Vasculogenesis and angiogenesis
The exudative form of advanced AMD is characterized by neovascularization and
hence it seems reasonable to search for genes that are involved in this process and
may carry variants which influence the development of wet AMD (Grisanti et al.,
2008). Vascular endothelial growth factor (VEGF) encodes a homodimeric glycol
protein, specifically produced by endothelial cells. It is a critical regulator of
vasculogenesis and angiogenesis and involved in the induction of permeability of
blood vessels. In addition VEGF is also required for normal maintenance of the
vasculature. Among the different members of the VEGF gene family, VEGF-A is the
most abundantly expressed and its nine different isoform are a result of differential
splicing. The VEGF-A 120 variant is the target of treatment with anti-VEGF
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antibodies (Macugen, Ranibizumab (Lucentis) and Bevacizumad (Avastin) of patients
with the wet/exudative form of AMD (Pieramici et al., 2008). Hypoxic conditions
(Fruttiger, 2007) as well as an imbalance of angiogenic and anti-angiogenic factors
(an example is pigment epithelium derived growth factor (PEDF)) can lead to retinal
or choroidal neovascularization (Bhutto et al., 2006). In a family-based and a case
control data set, DNA variants in VEGFA were shown to be associated with AMD
(Haines et al., 2006). In addition, a haplotype including nine DNA sequence variants
in the promoter of VEGFA also associates strongly with neovascular AMD within a
population of northern European origin (odds ratio of 18.24) (Churchill et al., 2006).
Furthermore, association was also found in an AMD patient population from Taiwan
with a sequence variant in the 3’UTR of VEGFA (Lin et al., 2008). Other attempts to
replicate association with VEGFA have failed, including the Rotterdam study
(Boekhoorn et al., 2008; Richardson et al., 2007). Heterogeneity in the patient
populations could account for these inconsistent findings. Nevertheless, further
investigations are required to fully understand the complexity of VEGFA involvement
in the exudative form of AMD.
In summary, the search for susceptibility loci has contributed a substancial number of
genes implicated in contributing to the risk of developing AMD but also with
protective effects. As approximately half of the number of genes studied yield
conflicting findings (Table 1 in reference Lotery and Trump (Lotery et al., 2007)
further components influencing AMD remain to be identified.
2.3
Generalized photoreceptor diseases (non-syndromic)
2.3.1 Leber congenital amaurosis (LCA)
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The retinal dystrophy designated Leber congenital amaurosis (LCA) is the most
severe in terms of visual loss and has a very early age of onset (<1 year of age). The
clinical features include congenital or early onset loss of vision, sensory nystagmus
and no light response upon electrophysiology (ERG). The frequency of the disease is
about 1 in 50000. The genetic heterogeneity of this disease is considerable.
Currently, 15 genes were identified to carry mutations in patients affected by this
disease (Figure 4, Table 5). The mode of inheritance of most of the mutations is
autosomal recessive. Dominant inheritance is discussed for sequence alterations in
CRX and IMPDH1. Functionally, the different gene products are involved in many
cellular functions including photoreceptor development and differentiation,
phototransduction, vitamin A metabolism and others. Recently, a review has been
published which summarizes clinical, genetic, diagnostic and also functional details
about this group of diseases (den Hollander et al., 2008). Because of the recessive
nature of most mutations, genetic homozygosity mapping is a particularly successful
approach in order to identify the underlying molecular basis of the disease within
families.
One of the genes which is associated with LCA was designated RPE65 (Marlhens et
al., 1997). It encodes a protein consisting of 533 amino acid residues with high
abundance in the retinal pigment epithelium. The protein is an isomerase and
involved in the conversion of all-trans retinol to 11-cis retinal. Gene transfer of the
RPE65 gene in the eyes of patients provides the first example for a successful gene
therapy in human patient with this severe form of retinal dystropohy (Bainbridge et al.,
2008; Hauswirth et al., 2008; Maguire et al., 2008), which is further described below.
2.3.2 Choroideremia
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Choroideremia (CHM) is an X-linked inherited retinal degeneration with an estimated
incidence rate of 1: 50,000. Symptoms begin with night blindness during teenage
years and the disease progressively affects degeneration of photoreceptor cells,
retinal pigment epithelial cells, the choriocapillaris and the choroid, leading to
complete blindness. This disease is caused by mutations in the REP1 gene
(Cremers et al., 1990; Merry et al., 1992), which encodes Rab escort protein-1. It
mediates prenylation of Rab GTPases and affects their involvement in intracellular
vesicular transport (Preising et al., 2004; Seabra et al., 1993). Among the numerous
reported mutations (McTaggart et al., 2002), which cause frameshift, nonsense or
splice site alterations, no missense mutations have been found. In contrast to
mutations that affect only the REP1 locus leading to non-syndromic CHM, large gene
deletions are known to cause syndromic phenotypes ((Poloschek et al., 2008) and
references therein). Although the gene is ubiquitously expressed, mutations affect
primarily retinal structures (Seabra et al., 2002). Expression of REP2 can
compensate for the loss of functional REP1, except in the ocular structures, which
leads to the specific eye phenotype (Cremers et al., 1994). This hypothesis is
supported by the recent finding that nonmammalian vertebrates do not have the
REP2 gene and hence REP1 mutations are lethal (Moosajee et al., 2009). The
disease-causing mechanism is still unclear but two models are discussed: a cascade
type effect on the three layers photoreceptors, RPE and choroids, or an independent
degeneration of them (Tolmachova et al., 2006).
2.3.3 Gyrate atrophy of the choroid and retina
Gyrate atrophy or ornithine aminotransferase deficiency, a slowly progressive
chorioretinal degeneration, is inherited in an autosomal recessive pattern. The ocular
symptoms include night blindness, myopia and a progressive loss of peripheral vision
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in the first decade of life, posterior subcapsular cataracts in the second and blindness
in the fourth to fifth decade. There might be a mild skeletal muscle weakness and
mental retardation but these extraocular symptoms are present only occasionally. An
arginine restricted diet (arginine is the precursor of ornithine) has been described to
be beneficial in some patients. However, the slow progression of the disease makes
it difficult to quantify the effect of treatment. The disease is caused by mutations in
the ornithine aminotransferase gene (OAT) on human chromosome 10 (Valle et al.,
1977). The disorder appears to be very rare with a higher incidence in Finnland (1
affected individual in 50000). The first mutation in this gene has been reported more
than twenty two years ago (Mitchell et al., 1988).
2.4
Vitreoretinopathies
2.4.1 Erosive vitreoretinopathies
This group of rare diseases encompasses pathological appearance of the vitreous
associated with retinal changes that may include the retinal pigment epithelium. We
count several hereditary diseases to this group which are traditionally known as
Stickler syndrome, snowflake vitreoretinal degeneration, Goldmann-Favre syndrome,
autosomal dominant vitreoretinochoroidopathy (ADVIRC), Wagner syndrome and
erosive vitreoretinopathy (ERVR) (Figure 5, Table 6). Due to most recent molecular
data, the latter two are now known as VCAN-related vitreoretinopathies (reviewed in
(Kloeckener-Gruissem et al., 2009). Vitreous syneresis, retinal changes with retinal
detachment, development of cataract, poor night vision, visual field defects and
abnormal ERG recordings, all of progressive nature, are clinical characteristics of
these vitreoretinopathies. In most patients, first signs become obvious during the late
teenage years. Restriction of visual acuity is among the first complaints of the
patients. The affected vitreous is frequently described as “empty” with veils and
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strands. Except in autosomal dominant vitreoretinochoroidopathy, retinal detachment
is a common accompanying feature of the phenotype. Clinically, the type of retinal
detachment frequently allows the distinction between the different vitreoretinopathies.
While tractional detachment is the more typical type in Wagner disease and erosive
vitreoretinopathy, the rhegmatogenous type of retinal detachment is characteristic for
Stickler syndrome and Snowflake vitreoretinal degeneration. In the following
sections we aim to discuss the specific phenotypes with their underlying molecular
basis.
Enhanced S-cone syndrome (ESCS)
ESCS patients show the rather unusual effect of gain of function of photoreceptors
with varying degrees of severity of retinal degeneration. The more severe type is
also known as Goldmann Favre syndrome (GFS). A liquefied vitreous body with
preretinal band-shaped structures, development of cataract, macular changes like
retinoschisis, pigment loss and a severely affected electroretinogram belong to the
typical clinical picture in GFS patients. The retina displays areas with thickened
layers localized to an annulus encircling the central fovea (Jacobson et al., 2004).
The patients have severely reduced numbers of rods and L and M type cone
photoreceptors but simultaneously they show an increased numer of S cone
photoreceptors (Milam et al., 2002). The molecular cause for this is most likely
related to recessive mutations in the nuclear receptor gene NR2E3, which encodes a
transcription factor whose expression pattern appears to be restricted to the outer
nuclear layer of the adult retina (Haider et al., 2000). Either single nucleotide
substitutions, in particular the R311Q substitution, or small deletions affecting the
coding region lead to an altered function of the transcription factor (Milam et al.,
2002). Patients carry either homozygous mutations or are compound heterozygous
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(Lam et al., 2007). Interestingly, all mutations map to evolutionary conserved protein
domains (Haider et al., 2000). Probably, mutations in NR2E3 cause abnormal cell
fate during development of the retina, leading to an excess of S-cones at the
expense of rods and L and M cones. In addition, a donor retina from a patient
carrying the R311Q mutation displayed severe structural disorganization such that
the cones were densely packed and interspersed with inner retinal neurons (Milam et
al., 2002). It remains subject to speculation how mutations in NR2E3 relate to the
vitreous syneresis typically found in GFS.
Snowflake vitreoretinal degeneration
The pattern of inheritance of this disease is also autosomal dominant. Patients show
early onset cataract, vitreoretinal dystrophy, fibrillar degeneration of the vitreous and
peripheral retinal abnormalities including shiny crystalline-like deposits resembling
snowflakes. Rhegmatogenous retinal detachment is observed. The first family with
snowflake vitreoretinal degeneration was originally described by Hirose et al (Hirose
et al., 1974) with a follow up description (Lee et al., 2003). Using DNA from affected
and unaffected members of this family a mutated nucleotide (c.484C>T, p.R162W) of
the gene KCNJ13 on chromosome 2 was found to segregate with the phenotype.
KCNJ13 encodes Kir7.1, member 13 of subfamily J of the potassium inwardly
rectifying channel family (Hejtmancik et al., 2008). Transcript analysis of KCNJ13
demonstrated expression in kidney and brain and within the eye in adult and neural
retina and RPE cells (Yang et al., 2008a). The mutation (484C>T, R162W) disrupts
the structure of the channel, which is the most likely cause for the retinal phenotype.
Understanding the vitreous phenotype remains a challenge since the channel has not
been shown to be a structural part of the vitreous (Hejtmancik et al., 2008).
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Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
This rare disease was first described by Kaufmann et al. (Kaufmann et al., 1982).
Characteristic fibrillar condensation within the vitreous is not accompanied by the
appearance of an optically “empty” vitreous, as described in patients with Wagner
syndrome. Furthermore, retinal breaks, retinal detachment, systemic or skeletal
abnormalities are also missing. Typical to this dease are the following features: a
hyperpigmented band of cells at the peripheral retina which is punctuated with white
opacities, the breakdown of the blood retinal barrier with retinal neovascularization,
presenile cataract and occasionally choroidal atrophy. Disease progression is very
slow (Kaufmann et al., 1982) but can be recognized by ERG measurements since
younger patients display a normal pattern that becomes moderately abnormal later in
life. Rod photoreceptor cells seemed more severely affected than cones (decreased
amplitude of a- and b-wave). An abnormal electro oculogram suggested a defect at
the level of the RPE. Mutations in the gene VMD2, which is expressed in the RPE,
were found to cause ADVIRC (Yardley et al., 2004). VMD2 encodes bestrophin, a
trans-membrane protein expressed in the RPE. It was first found to be involved in
Best disease (vitelliform macular dystrophy, which is described elsewhere in this
review). All VMD2 mutations are exonic and were found to cluster, irrespective of the
different diseases, to regions in the trans-membrane domains (Table 7).
Table 7: Neighboring VMD2 mutations cause different disease phenotypes.
Mutation
c.253T>C
c.256G>A
c.707A>G
c.715G>A
c.727G>A
Protein
p.Y85H
p.V86M
p.V89A
p.V235L
p.V235M
p.Y236C
p.T237R
p.V239M
p.T241N
Disease
Best disease
ADVIRC
Best disease
Best disease
Best disease
ADVIRC
Best disease
ADVIRC
Best disease
Effect
no effect on splicing
novel splice variants
novel splice variants
novel splice variants
no effect on splicing
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To explain how the closely spaced missense mutations can result in these two
different phenotypes, Yardly et al. hypothesized that splicing might be affected via
exonic splicing regulatory elements (Yardley et al., 2004). This hypothesis could be
verified by using an in vitro mini gene functional assay. Production of novel splice
variants was specific only for those mutations causing ADVIRC, but not for the
neighboring Best disease causing mutations. With this high degree of genotypephenotype correlation the authors suggest that the abnormal splice products have a
novel effect on ocular development (Yardley et al., 2004).
Wagner syndrome and erosive vitreoretinopathy
Wagner syndrome was first described in 1938 as a non systemic ocular abnormality
(Wagner, 1938). The clinical appearance of patients with Wagner syndrome includes
syneresis of the vitreous, cataract, high myopia, night blindness and retinal
detachment and has been reviewed recently (Kloeckener-Gruissem et al., 2009).
Linkage analyses revealed a region on chromosome 5 to which a candidate gene,
VCAN (formerly CSPG2), encoding the extracellular matrix protein versican, localized
(Brown et al., 1995; Perveen et al., 1999). It still took several years until the first
causative mutation in VCAN was identified in a Japanese family with Wagner disease
(Miyamoto et al., 2005), which was followed by the identification of further mutations
in the original Wagner family (Kloeckener-Gruissem et al., 2006) as well as in
additional families (Meredith et al., 2006; Mukhopadhyay et al., 2006; Ronan et al.,
2009). All mutations localize to splice donor or acceptor sites that affect splicing of
exon 8. VCAN is expressed in the vitreous and in cartilage and exists in four splice
variants that differ in the presence or absence of exon 7 and exon 8. The levels of
VCAN variant V2 (no exon 8) and V3 (no exon 7) transcripts from patients’ blood or
lymphoblastoid cell lines are highly elevated (Mukhopadhyay et al., 2006), indicating
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quantitative alterations of the naturally occurring splice variants as possible
pathogenic mechanism.
A family with ERVR was also found to segregate a splice site mutation in VCAN
(Mukhopadhyay et al., 2006), suggesting that the two syndromes, Wagner and ERVR,
are allelic, as it was previously anticipated based on mapping data (Black et al., 1999;
Brown et al., 1994; Brown et al., 1995; Mukhopadhyay et al., 2006). Diagnostic
mutation screening can benefit tremendously from these findings as sequencing of
the rather large exon 7 (2.961 kb) and exon 8 (5.262 kb) can initially be avoided by
focusing on intron-exon sequences of exon 7 and exon 8.
2.4.2 Exudative vitreoretinopathies (EVRs)
EVR is characterized by an incomplete blood vessel development in the retinal
periphery, as well as by retinal folds and retinal detachment. The clinical diagnosis is
usually made in the first years of life. There may be a decreased visual acuity due to
macular folds or detachment. Upon fluorescein angiography, the retinal periphery
appears avascular. A fibrovascular mass may develop that is associated with retinal
exudates. This mass may extend to the ciliary body and peripheral lens capsule. The
clinical manifestations are highly variable and some patients do not experience
dramatic visual impairment. The inheritance patterns include autosomal dominant
and recessive as well as X-linked transmission of the mutations. Currently three
genes are known to carry mutations (Figure 5, Table 6) but there might be additional
genetic defects in other genes. The first gene identified in this disease is the X-linked
Norrie disease pseudoglioma gene (NDP) (Chen et al., 1993). Mutations in this gene
lead usually to a severe disease, designated Norrie disease (ND) (Berger et al.,
1992a; Berger et al., 1992b; Berger, 1998; Chen et al., 1992; Meindl et al., 1992).
This disease is characterized by congenital blindness and progressive hearing
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The molecular basis of human retinal and vitreoretinal diseases
impairment, starting in the first or second decade of life. In some cases, mental
retardation or autistic features and behavioral manifestations are observed. Since
mutations are X-linked recessive, only males are affected although exceptions exist,
where female carriers also show symptoms (Sims et al., 1997; Yamada et al., 2001).
There is a wide spectrum of mutations in this gene (please refer to the following
website, where more than 100 mutations are summarized:
http://www.medmolgen.uzh.ch). Remarkably, the same amino acid substitution can
lead to either classic Norrie disease or EVR. For example the mutation p.R121W
results in classic or mild ND, but was also found in EVR (Kellner et al., 1996; Meindl
et al., 1995; Shastry et al., 1995; Shastry et al., 1997a; Wu et al., 2007). The same
amino acid substitution was reported to be associated with retinopathy of prematurity
(Shastry et al., 1997b), which is not a monogenetic trait but also might involve
genetically predisposing factors.
Similar observations were reported in the literature for other amino acid substitutions
in the NDP gene, for example p.I18K, p.R38C, p.K54N, p.K58N, p.R74C, p.C96Y
and p.R121Q, all of which are associated with Norrie disease or EVR (Berger et al.,
1992b; Boonstra et al., 2009; Fuchs et al., 1996; Fuentes et al., 1993; Kondo et al.,
2007; Meindl et al., 1992; Meindl et al., 1995; Riveiro-Alvarez et al., 2005; Royer et
al., 2003; Shastry et al., 1999; Shima et al., 2009). Because of the frequent reports of
a variable clinical expressivity or manifestations of different mutations, it is difficult to
predict the clinical course of the disease for a specific mutation.
In addition to NDP, three other genes were found to be mutated in EVR: Frizzled-4
(FZD4) (Robitaille et al., 2002), the low density lipoprotein receptor-related protein 5
gene (LRP5) (Jiao et al., 2004), and tetraspanin 12 (TSPAN12) (Nikopoulos et al.,
2010; Poulter et al., 2010). Similar to NDP mutations, pathogenic LRP5 sequence
alterations also lead to extra ocular symptoms. The disease is designated
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osteoporosis pseudoglioma syndrome (OPPG). FZD4 mutations are dominant while
LRP5 mutations are recessive, although a bone phenotype can be present in LRP5
mutation carriers.
These four genes and their proteins are functionally linked. It was found that Norrin is
a ligand of the receptor pair FZD4 and LRP5. Upon Norrin binding, the canonical Wnt
signaling pathway is induced in the target cell (Xu et al., 2004). This was shown by
using reporter gene assays in cell culture. The functional interaction of Norrin, FZD4,
LRP5 and TSPAN12 during retinal angiogenesis is also supported by phenotypic
similarities observed in human patients but also in the respective mouse models
(Berger et al., 1996; Hsieh et al., 2005; Junge et al., 2009; Luhmann et al., 2005b;
Luhmann et al., 2005a; Luhmann et al., 2008; Schäfer et al., 2008; Wang et al., 2001;
Ye et al., 2009).
3.
Syndromic retinal diseases
3.1
Usher syndrome
In Usher syndrome, not only the retina is affected by the disease but also the inner
ear. The disease is a combination of retinitis pigmentosa (RP) and sensorineural
deafness or hearing impairment. Clinically, Usher syndrome is classified in three
subtypes, depending on the severity and age of onset of disease manifestations in
retina and ear. The most severe form is Usher syndrome type 1. Patients with this
subtype have profound and congenital deafness and vestibular dysfunction, leading
to delayed motor development, and adolescent-onset RP. Usher type 2 is less
severe with normal vestibular function, mild to severe sensorineural hearing loss,
which is non-progressive in most cases, and a later onset of RP in adolescence or
adulthood. Patients with Usher 3 also have a milder but progressive form of deafness
and approximately 50% also manifest vestibular problems. The mode of inheritance
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for all three types of Usher syndrome is autosomal recessive. It accounts for
approximately half of the cases of deaf-blind patients (Vernon, 1969) and affects
between 1:12000 or 1:30000 people in different populations. The general frequency
of RP is about 1 in 3000 to 1 in 5000 individuals, the Usher cases may represent
between 10-30% of all autosomal recessive RP cases (Hartong et al., 2006). So far,
mutations in 10 different genes (Figure 2, Table 8) have been associated with Usher
syndrome (Bolz, 2009; Saihan et al., 2009; Williams, 2008). Two major loci for Usher
type 1 and 2 are myosin 7A (MYO7A) and usherin (USH2A), respectively (Eudy et al.,
1998; Weil et al., 1995). MYO7A mutations account for 30-50% of Usher 1 cases.
The gene product is an actin-based motor protein. In addition to its motor domain,
this exceptionally large protein (5202 amino acid residues) also contains additional
domains which are responsible for the interaction with other cellular proteins and may
be responsible for the intracellular transport of proteins through the connecting cilium
of photoreceptor cells. This is supported by the abnormal accumulation of opsin
within the connecting cilium in Myo7a-deficient mice (Liu et al., 1999). Usherin
(USH2A) is most likely a membrane anchored extracellular protein which is important
for photoreceptor cell maintenance and proper development of sensory hair cells
within the cochlea (Liu et al., 2007). The Usher-associated proteins form a complex
network which is important for protein transport in photoreceptor and hair cells. Usher
1D (cadherin 23) and 1F (protocadherin-15) are cell adhesion molecules and might
be important for the structural integrity of the tissue.
3.2
Bardet Biedl syndrome
Bardet-Biedl syndrome (BBS) is caused by mutations in at least 13 genes (see
Figure 2, Table 8) (Ansley et al., 2003; Badano et al., 2003a; Chiang et al., 2006; Fan
et al., 2004; Katsanis et al., 2000; Li et al., 2004; Mykytyn et al., 2001; Mykytyn et al.,
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2002; Nishimura et al., 2001; Nishimura et al., 2005; Stoetzel et al., 2006; Stoetzel et
al., 2007). The phenotypic variability among patients, even within one family, is
significant. The primary features include retinal degeneration, obesity, polydactyly,
renal and genital abnormalities, and learning disabilities. A number of secondary
features, e.g. situs inversus, developmental delay, diabetes mellitus, and strabismus,
have also been observed in BBS patients (compare www.geneclinics.org or
(Katsanis et al., 2001b)).
In a surprisingly short time period of around 8 years, 12 genes have been associated
with BBS. This was even more surprising since the disease is rare and affects only 1
individual in 120000 Caucasians. Isolated populations with an increase in
consanguinity accelerated gene identification using linkage or homozygosity mapping.
The first gene has been discovered in the year 2000 on the basis of linkage in
Newfoundland families. Linkage intervals suggested overlapping mapping positions
with the clinically similar McKusick-Kaufman syndrome gene MKKS. Co-segregation
of mutations in BBS6 patients within the MKKS gene confirmed that the two
syndromes are allelic (Katsanis et al., 2000), but genetic heterogeneity suggested the
existence of additional BBS genes. Combining classical genetic mapping
technologies with an in silico-based method of comparing genomes of ciliated and
non-ciliated species allowed the identification of BBS3, BBS5, and BBS9.
Furthermore, BBS7 as well as the causative gene within the BBS1 locus were
discovered on the basis of protein homology with BBS2. Protein comparisons also
lead to the identification of BBS8, which shows sequence similarity to BBS4.
Moreover, the predicted function of the gene product of BBS6/MKKS as a
chaperonin-like molecule led to the identification of the most recently discovered
BBS-associated gene BBS12; the sequence homology to chaperonins indicated a
priority for a candidate within the linkage interval of consanguineous families
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The molecular basis of human retinal and vitreoretinal diseases
(Stoetzel et al., 2007). Moreover, BBS10 is also a possible chaperonin (Stoetzel et al.,
2006). Evolutionary conservation indicated that BBS 6, 10, and 12 are part of a
separately evolved branch of the chaperonin gene family and thus might be involved
in protein folding. Nevertheless, protein folding seems not to be the main function
linking all BBS genes. A large body of work rather indicates that ciliary transport and
basal body properties are disturbed in BBS patients. This observation is also
supported by a number of clinical phenotypes, e.g. situs inversus (caused by
disturbed ciliary function in the node of the developing embryo), as well as renal
cysts (induced by dysfunction of cilia in the renal tubule or retinitis pigmentosa
causes by inhibition of transport processes through the connecting cilium of the
photoreceptor). Indeed, BBS1 is associated with vesicular transport processes of the
cilium, indictated by the finding that BBS1 binds to Rabin-8 which in turn activates
rab-8, a molecule that targets vesicles to cilia (Nachury et al., 2007). A similar
process might also affect transport efficiencies across the photoreceptor connecting
cilium and cause retinal degeneration. This hypothesis is supported by the finding
that rhodopsin is less efficiently transported from the inner segment to the outer
segment of rod photoreceptors in BBS2 knock out mice (Nishimura et al., 2004).
Furthermore, complexes containing chaperones, rhodopsin, and other photoreceptorspecific proteins have been associated to intraflagellar transport processes through
the connecting cilium of rods (Bhowmick et al., 2009).
Disturbed transport processes across cilia may even influence basic cellular signaling
cascades, as exemplified by the finding that a BBS4 knock down resulted in reduced
inhibition of the canonical Wnt signaling pathways after stimulation with the Wnt
effector Wnt3a (Corbit et al., 2008; Gerdes et al., 2007). However, the exact
mechanism underlying the connection between cilia and Wnt signaling is not
completely understood (He, 2008).
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Typically, BBS mutations are autosomal recessive. The most frequently mutated BBS
gene is BBS1, which affects over 20% of the patients (Katsanis, 2004). Moreover, the
hot spot mutation p.M390R is found in up to 80% of BBS1 patients (see
www.geneclinics.org). The second most frequent hot spot mutation p.C91LfsX4 in
BBS10, which affects around 50% of the BBS10 alleles. Thus, a significant portion of
the cases can be identified by screening only 2 exons in two BBS genes.
Nevertheless, 20-30% of the patients have no detectable mutations in the known
genes (see www.geneclinics.org), which strongly indicates that further BBS genes
await identification.
In some pedigrees the disease does not follow the classical autosomal recessive
pattern, but seems to be transmitted in a digenic or oligogenic way. Individuals have
been documented who showed two mutations in a single BBS gene in addition to a
sequence alteration in a different BBS gene (Beales et al., 2003). Further support for
the digenic or oligogenic inheritance is provided from individuals who carry two
known mutations in BBS1 (p.M390R) without expressing the phenotype. Significantly,
a case has been identified where only three nonsense mutations in two different BBS
genes cause disease manifestations while two nonsense mutations on both alleles of
a single gene do not lead to symptoms (Katsanis et al., 2001a). Nevertheless, in
cases with oligogenic inheritance, the third mutation is often a missense mutation
with uncertain pathogenicity. This may also indicate that additional mutations act as
modifiers influencing the degree of phenotypic expression in patients (Badano et al.,
2003b). Consequently, different disease severities might be explained depending on
the particular ‘BBS environment’ of the individual patient. The molecular basis for
such ‘BBS environments’ has been reported (Nachury et al., 2007). Nachury et al.
showed that seven BBS proteins build an interaction complex, called the BBSome.
Using BBS4 as bait, stoichiometric amounts of BBS1, BBS2, BBS5, BBS7, BBS8,
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and BBS9 have been isolated within a cilia-associated complex. Inhibition of
members of the BBSome leads to disturbed ciliary properties. Thus, it may well be
that additional mutations within the BBSome affect the phenotypic presentation of the
respective patient. It will be interesting to further analyze these complex correlations,
e.g. by crossing the homozygous BBS1 p.M390R knockin mouse model (Davis et al.,
2007) into different genetic backgrounds to determine the influence of modifiers for
the disease expression. Alternatively, generating double or tripple knockout BBS
mice might provide further clues to the genetic interaction between BBS genes and
their consequences for the phenotype. In the light of modifier action or oligogenetic
inheritance, it is interesting that while most BBS patients show severe retinal
degeneration, mild forms have also been reported (Azari et al., 2006; Gerth et al.,
2008; Heon et al., 2005). In addition, different phenotypic expressions like retinitis
pigmentosa and macular degeneration were reported in patients with a homozygous
BBS1 mutation p.M390R (Azari et al., 2006). This heterogeneity of the phenotype
may be best understood through the action of genetic modifiers.
Analogous to the oligogenic influence on the BBS phenotype, other cases of RP or
retinal degeneration are likely to be influenced by modifiers. As an example,
mutations in the RPGR gene may cause X-linked recessive RP, but occasionally is
associated with additional phenotypes like hearing defects, primary ciliary dyskinesia,
or sinorespiratory infections (Iannaccone et al., 2003; Moore et al., 2006; Zito et al.,
2003). Furthermore, the disease expression largely varies even within one family.
Since RPGR binds a number of retinal degeneration-associated interaction partners
at the molecular level (e.g. RPGRIP1, SMC1 and 3, CEP290 or Nephrocystin 5), it
seems plausible that modifying sequence alterations affecting the ‘RPGR
interactome’ would give rise to altered phenotypic severity or additional clinical
manifestations.
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3.3
Senior Loken Syndrome / Nephronophthisis (SLSN)
Patients with SLSN manifest kidney and eye diseases. The kidney phenotype is
designated nephronophthisis (NPHP) and the retinal degeneration can be RP of
varying degrees or LCA, as in the case of NPHP6/SLSN6. So far, six genes were
shown to carry mutations in affected individuals (Figure 2, Table 8). Recent studies
have shown that the respective gene products are involved in the structure or
function of motile and primary cilia. Therefore the term ´ciliopathies´ is also used for
this group of diseases, as it is for primary ciliary dyskinesias. Most prevalent are
mutations in the NPHP1/SLSN1 gene, which were found in approximately 20% of the
families. All other genes are affected significantly less frequent (0.1-3%) (Hildebrandt
et al., 2009). NPHP1/SLSN1 localized to the transition zone of the cilium and were
found to interact with other proteins which can carry mutations in patients with Senior
Loken syndrome, including inversin, nephrocystin-3 and nephrocystin-4 (Fliegauf et
al., 2006; Mollet et al., 2002; Olbrich et al., 2003; Otto et al., 2003). Although
molecular diagnosis is possible in some families, the majority of cases
(approximately 70%) can not be explained by mutations in the genes known so far.
3.4
Refsum disease
Refsum disease belongs to the peroxisome biogenesis disorders (PBD), which also
include Zellweger syndrome, neonatal adrenoleukodystrophy, and rhizomelic
chondrodysplasia punctata. The first symptoms may arise during late childhood and
include defective night vision, progressive RP, mental retardation, and anosmia.
During disease progression additional features like polyneuropathy, deafness, ataxia,
cardiac arrhythmias as well as skin abnormalities (ichthyosis) may establish. In
addition, about one third of patients have bone manifestations in hand and feet
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(Jansen et al., 2004). Mutations in five genes were detected in affected individuals
(Figure 2, Table 8) (Furuki et al., 2006; Geisbrecht et al., 1998; Jansen et al., 2004;
Matsumoto et al., 2003; Shimozawa et al., 1999). The functional spectrum of these
genes comprises fatty acid oxidation, peroxisomal protein import as well as
peroxisome biogenesis.
3.5
Joubert syndrome
Joubert syndrome is a rare (1/100000) clinically and genetically heterogeneous group
of developmental disorders, which is inherited in an autosomal recessive pattern.
One exception has recently been described with an X-linked recessive mode of
inheritance (Coene et al., 2009). Characteristic features are hypoplasia of the
cerebellar vermis with the neuroradiologic “molar tooth sign” and other neurologic
symptoms including dysregulation of breathing pattern and a general developmental
delay. Additional variable features which include polydactyly, hepatic fibrosis, renal
disease and retinal dystrophy are often collectively referred to as cerebello-oculorenal syndrome (CORS), which is also associated with primary ciliary dysfunction.
The clinical heterogeneity is reflected by genetic heterogeneity as eight genes have
been described to be involved in Joubert syndrome (Figure 2, Table 8). Generally,
mutations in one of the eight genes do not necessarily lead to all possible
phenotypes. Mutations in the Abelson’s helper integration 1 gene (AHI1) also known
as JBTS3 (Dixon-Salazar et al., 2004; Ferland et al., 2004) are associated mainly
with symptoms restricted to the central nervous system. Several exceptions were
reported where patients who carried mutations in AHI1 showed in addition a retinal
phenotype that could range from RP to LCA (Valente et al., 2006). Although the
function of the AHI1 protein is not known, the presence of a putative Src homology 3
(SH3) domain and six WD40 repeats suggests that AHI1 mediates the formation of
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large multi-protein complexes. Furthermore, the AHI1 protein may play also a role in
common disorders that affect cognition and behavior since sequence variants of
AHI1 were found to associate with autism (Alvarez Retuerto et al., 2008). Deletion
mutations in another gene, NPHP1, also known as JBTS4, have been found in few
patients with Joubert syndrome (Valente et al., 2006) and Senior-Loken syndrome
(SLSN), a recessive form of RP (Caridi et al., 1998), although most mutations are
responsible for isolated juvenile nephronophthisis. SLSN will be described elsewhere
in this review. The gene product of NPHP1 is nephrocystin-1 and with the help of
mouse models its role in intraflagellar transport could be demonstrated (Jiang et al.,
2009). Another component of the ciliary complex is a putative 2480-residue
centrosomal protein encoded by CEP290. Mutations in this gene were associated
with several aspects of Joubert syndrome, including those of retina and kidney
(Brancati et al., 2007; Valente et al., 2006). The severity of the ocular phenotype in
these patients is similar to that characteristic of the Senior-Loken syndrome. It is
noteworthy that mutations in CEP290 have been shown to be the most frequent
cause of isolated LCA, in the absence of any renal or neurological involvement (den
Hollander et al., 2006; Perrault et al., 2007). Interestingly, one Joubert patient with a
homozygous deletion affecting exon 36 of CEP290 showed the LCA ocular
phenotype and complete situs inversus, suggesting a strong overlap between
Joubert syndrome and other ciliopathies (Brancati et al., 2007). This overlap is
further supported by association of mutations in the gene CC2D2A with Joubert
syndrome, including retinal defects. The CC2D2A product interacts in vitro with the
CEP290 protein (Gorden et al., 2008) and both proteins localize to the basal body.
Mutations in the gene ARL13B, encoding a further ciliary protein, ADP-ribosylation
factor-like protein13B, can also lead to Joubert syndrome (Cantagrel et al., 2008).
ARL13B’s involvement in the retinal defect in Joubert syndrome has not been
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completely understood since only one Joubert syndrome patient displayed evidence
of mild pigmentary retinopathy but normal ERG. Finally, the gene RPGR-interacting
protein 1-like (RPGRIP1L), encoding a ciliary protein with specificity for the cilium of
photoreceptors, is mutated in patients with CORS; among them also one patient with
retinitis pigmentosa (Delous et al., 2007). Further screening did not yield additional
individuals with retinitis pigmentosa, making it likely that mutations in this gene are
largely confined to the cerebro-renal subgroup of Joubert syndrome (Brancati et al.,
2008). Frameshift mutations in the gene OFD1, which is known for its association
with oral-facial-digital syndrome type 1, were recently found in a family segregating
X-linked Joubert syndrome with RP (Coene et al., 2009). As the previous examples
showed, OFD1 also interacts with a component of the ciliary protein complex.
Depending on the dominant or recessive phenotype, interaction with LCA5 encoded
ciliary protein lebercillin either abolishes or reduces binding (Coene et al., 2009).
These examples demonstrate the necessity of a functional ciliary complex and
intraflagellar transport for normal retinal function. The findings also emphasize the
genotypic-phenotypic complexity of the syndromic diseases with retinal involvement
as stated elsewhere through out this review. Most recently, mutations in the gene
TMEM216, coding for a short protein of 87 amino acids predicted to form two
transmembrane domains, were associated with Joubert syndrome type 2 (Edvardson
et al., 2010). It is speculated, that it is part of the primary cilium, similar to TMEM67,
which is also involved in Joubert syndrome (Baala et al., 2007; Dawe et al., 2007).
3.6
Alagille syndrome (ALGS)
Mutations in jagged 1 (JAG1) and the notch 2 receptor cause Alagille syndrome
(ALGS1 and ALGS2, Figure 4, Table 5)(McDaniell et al., 2006; Oda et al., 1997). The
majority of cases can be explained by sequence alterations in JAG1. JAG1 is a
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The molecular basis of human retinal and vitreoretinal diseases
transmembrane protein that constitutes a ligand in the notch pathway. Since the
notch signalling is an important developmental pathway, relevant for several tissues
(reviewed by (Kopan et al., 2009), it is not surprising that ALGS1 includes a wide
range of clinical manifestations (hepatic, cardiac, vascular, skeletal, ocular, facial,
renal, pancreatic, and neuronal) (Piccoli et al., 2001). Clear genotype-phenotype
correlations have not been observed in ALGS. Moreover, the phenotypes are highly
variable among patients with JAG1 mutations (Colliton et al., 2001). Ocular features
of ALGS may include optic disc drusen, angulated retinal vessels, a pigmentary
retinopathy, and posterior embryotoxon (Kim et al., 2007). The disease is rare and
affects approximately 1 in 100000 individuals. The mutations are inherited in an
autosomal dominant pattern with reduced penetrance. Interestingly, the majority of
the JAG1 mutations are nonsense mutations or small deletions leading to premature
termination codons. Furthermore, some deletions affect the entire coding region of
JAG1. This supports the hypothesis that a reduced gene dosage (haploinsufficiency)
may be the basis of the disease (Spinner et al., 2001).
3.7
Alstrom syndrome (ALMS)
Alstrom syndrome is a rare (less than 200000 affected individuals in US population)
autosomal recessive disorder characterized by a progressive cone-rod photoreceptor
dystrophy, sensorineural hearing loss, obesity and type II diabetis. In many patients
cardiomyopathy, urological dysfunction and pulmonary, hepatic and renal failure
develop as well. Despite its similarities to Bardet-Biedl syndrome, mental retardation,
polydactyly and hypergonadism do not belong to the repertoire of features in Alstrom
syndrome. Disruption of the gene ALMS1 (Figure 3, Table 3), located on
chromosome 2, was found to associate with the syndrome (Collin et al., 2002; Hearn
46
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et al., 2002). The gene does not share identifiable homologies to other known genes
or proteins and the proteins´ function is unknown (Marshall et al., 2007). ALMS1 is
widely expressed and the protein subcellularly localizes to centrosomes and basal
bodies of ciliated cells (Collin et al., 2002; Hearn et al., 2002). Among the identified
mutations are nonsense and frame shift variations that are predicted to result in
prematurely terminated proteins (Marshall et al., 2007). Exon 16 appears to contain
a mutation hotspot as evidenced by the fact that 12% of all mutant alleles carry the
deletion c.10775delC (Marshall et al., 2007). Patients with mutations in exon 16 also
seem to express a more severe phenotype (Marshall et al., 2007). Phenotypegenotype correlations were suggestive between alterations in exon 16 and the retinal
degeneration feature, if it manifested before the age of one year (Marshall et al.,
2007). Alm1 knockout mice aided in an attempt to understand the function of ALMS1.
With respect to the retinal phenotype, reduced b-wave responses in the ERG were
observed that were followed by photoreceptor degeneration. Accumulation of
intracellular vesicles in the inner segments and mislocalization of rhodopsin to the
outer nuclear layer indicate that ALMS1 may play a role in intracellular trafficking
(Collin et al., 2005). As the morphological appearance of the cilia was not altered (Li
et al., 2007) it seems likely that a functional rather than structural effect may be
responsible for the phenotype.
3.8
Neuronal ceroid lipofuscinosis (NCLs or CLNs)
Neuronal ceroid lipofuscinosis are neurodegenerative lysosomal storage diseases.
They are characterized by the accumulation of autofluorescent material in different
cell types including neurons. Clinical manifestations comprise epileptic seizures,
progressive psychomotor retardation, visual loss, and premature death. Mutations
occur in at least eight different genes (Figure 4, Table 5). The mode of inheritance is
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autosomal recessive. The age of onset is variable and defines, together with clinical
manifestations, five different forms of NCLs (Kousi et al., 2009): 1. congenital form
(CLN10), 2. infantile form (INCL, CLN1), 3. late infantile form (LINCL, CLN2), 4.
juvenile form (JNCL, CLN3), and 5. the adult form (ANCL, CLN4). Some of these
forms are genetically heterogeneous in terms of genes where mutations have been
described which lead to the clinical symptoms.
The infantile and late infantile forms are caused by mutations in the genes encoding
the lysosomal enzymes palmitoyl-protein thioesterase 1 (PPT1) and tripeptidyl
peptidase (TPP1), respectively (Sleat et al., 1997; Vesa et al., 1995). Mutations in the
gene coding for cathepsin D, a lysosomal proteinase, were found in patients with
congenital as well as later-onset NCLs (Fritchie et al., 2009; Siintola et al., 2006;
Steinfeld et al., 2006). Other NCL-associated genes encode lysosomal or
endoplasmic reticulum proteins. CLN3 seems to be a lysosomal membrane protein
(International Batten Disease Consortium, 1995; Jarvela et al., 1998). CLN5 is
expressed in cerebellar Purkinje cells, cerebral neurons, hippocampal pyramidal cells,
and hippocampal interneurons. Thus, the expression pattern correlates with
degenerated brain regions in CLN5 patients. Cell culture experiments revealed that
CLN5 is a soluble lysosomal glycoprotein (Holmberg et al., 2004; Isosomppi et al.,
2002). The CLN6 protein localized to the membranes of the endoplasmic reticulum
(Gao et al., 2002; Heine et al., 2004; Mole et al., 2004). The CLN7 gene codes for
the lysosomal transporter MFSD8 (Siintola et al., 2007) and CLN8 for a membrane
protein that localizes to the ER and ER-Golgi intermediate structure (Lonka et al.,
2000; Ranta et al., 1999).
3.9
Primary ciliary dyskinesia (PCD)
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PCD is a rare, autosomal recessive disease with a defect in ciliary function.
Progressive sinopulmonary disease is one of the cardinal features and approximately
half of the patients have situs inversus (mirror orientation of thoraco-abdominal
organs). Also male infertility is common and complex congenital heart disease can
occur (Leigh et al., 2009a; Leigh et al., 2009b). The combination of situs inversus
totalis, chronic sinusitis and bronchiectasis is also known as the Kartagener triad.
Almost all men with PCD are infertile from sperm immotility. Additional symptoms or
clinical manifestations may include hydrocephalus, retinitis pigmentosa, polycystic
kidney disease, liver cysts, biliary artresia. All those features are rare in PCD. Six
genes are known to be mutated in PCD disease (Figure 2, Table 8) (Bartoloni et al.,
2002; Failly et al., 2008; Guichard et al., 2001; Ibanez-Tallon et al., 2002; Loges et al.,
2008; Omran et al., 2008; Pennarun et al., 1999; Schwabe et al., 2008). In addition to
these genes an RPGR mutation was reported that leads to a combination of RP and
PCD (Moore et al., 2006). Mutations in DNAI1 and DNAH5 are responsible for about
half of the cases, while mutations in the other genes are rare (Escudier et al., 2009).
3.10
Stickler syndrome
Among the vitreoretinopathies Stickler syndrome may be the most frequent one and
unlike the others, it shows syndromic characteristics. The pattern of inheritance is
autosomal dominant, with one published exception (Van Camp et al., 2006). The
syndrome is a connective tissue disorder that can include eye, ear, joints and facial
features (www.genereviews.org). Hearing problems can be conductive and
sensorineural. Craniofacial features may include midface hypoplasia, depressed
nasal bridge, anteverted nares, micrognathia, cleft palate and glossoptosis. The joint
problems display hypermobility, mild spondyloepiphyseal dysplasia and also
precautious osteoarthritis. Here we will focus on the ocular features which include
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myopia, cataract, vitreous anomalies and retinal detachment (also known as
rhegmatogenous retinal detachment or RRD). The symptoms vary widely within and
among Stickler families and individuals (Donoso et al., 2003) and some overlapping
features with respect to the vitreous and retinal detachment have been observed with
Marshall syndrome (OMIM 154780). Based on the genetic cause and the pattern of
inheritance different types of Stickler syndrome can be distinguished (Figure 5, Table
6). Collagen plays an important role in the disease pathology of all types as has
become clear from mutation analyses. The autosomal recessive form involves the
COL9A1 gene (Van Camp et al., 2006) while the autosomal dominant form is caused
by mutations in COL2A1, COL11A1 and COL11A2, all encoding different types of
collagen (type II and type XI) constituting major components of the structural entities
of cartilage and the vitreous. Mutations in the latter gene do not seem to affect the
vitreous (Sirko-Osadsa et al., 1998). Additional Stickler loci are expected as not all
families could be identified with mutations (Richards et al., 2002). A potential
candidate is the gene encoding the nuclear protein TIA-1, which regulates alternative
splicing of COL2A1 (McAlinden et al., 2007).
Mutations in COL2A1 comprise the majority of the genetic causes of Stickler
syndrome. In a tissue-specific event, COL2A1 transcripts undergo alternative
splicing such that exon 2 containing transcripts are found in the vitreous and those
lacking exon 2 in cartilage. While mutations anywhere in the gene might give rise to
both, systemic and ocular manifestation, one might expect that mutations in or near
exon 2 would cause only ocular features. Clinical heterogeneity can only to some
extent be correlated with mutations in exon 2 (Donoso et al., 2003; McAlinden et al.,
2008), which is supported by the finding that the ocular phenotype is predominantly
caused by premature termination codon (PTC) mutations in exon 2. The same effect
on splicing but via a different mechanism causes the c.170G<A (p.Cys57Tyr)
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substitution, which lies within a cis regulatory region involved in splicing of the mature
transcript (McAlinden et al., 2008). Interestingly, a change of the same amino acid to
a stop codon (p.Cys57Stop) was associated with Wagner syndrome (Gupta et al.,
2002). Since the two diseases share many similarities, the diagnosis may have been
ambiguous (Richards et al., 2005). Taken together, differential splicing seems to be
an important molecular mechanism for tissue-specific diseases, as has been
observed for other syndromic diseases with ocular involvement and were discussed
under RP. Although haploinsufficiency is the proposed disease mechanism for
Stickler syndrome, missplicing leads frequently to a dominant-negative effect with a
more severe phenotype (Richards et al., 2005).
Mutations in COL11A1 are predicted to disrupt or alter collagen type XI. Among them
are few deletion and insertion mutations but the majority of mutations affect splice
sites at different intron-exon boundaries (Majava et al., 2007). We interpret that the
effect of these mutations is comparable to those described above for COL2A1.
The question whether different, yet often overlapping features of disease conditions,
are due to allelic states of a given gene can be answered by mutation analysis.
Using this approach, Marshall syndrome, which includes vitreous and retinal
abnormalities, can be considered allelic to Stickler syndrome since mutations in
COL11A1 cause both (Majava et al., 2007).
4.
Genetic testing and counselling
In order to diagnose and counsel patients and their families, knowledge about their
disease-causing mutation is essential. Especially for genetic counseling, targeted
clinical characterization and gene therapeutic interventions, the precise molecular
diagnosis is very important. Unfortunately, the disease-causing mutation is often
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difficult to identify due to the genetic heterogeneity and clinical variability of retinal
diseases.
Several strategies do exist and novel technologies are emerging that increase the
chance to identify the causative mutation in patients. For this purpose, knowledge of
the pedigree is of utmost importance. It often provides significant clues to the
selection of genes implicated for molecular genetic testing. In cases of autosomal
dominant RP, the likelihood to identify the causative mutation among the five most
frequently affected genes is approximately 50%. These five genes are rhodopsin
(RHO), peripherin 2 (PRPH2), retinitis pigmentosa 1 (RP1), pre-mRNA processing
factor 31 (PRPF31), and inosine monophosphate dehydrogenase 1 (IMPDH1). The
best candidate for adRP is rhodopsin, which accounts for up to 30% of the cases
(Kennan et al., 2005), whereas the other candidates have frequencies between 5 and
20%. Moreover, these five adRP genes comprise a total of only 40 coding exons, a
number that seems manageable to be analyzed by conventional sequencing or other
appropriate methods. Nevertheless, in cases of incomplete penetrance (carriers of
the mutation are occasionally not affected), the collection of candidate genes is much
smaller. Only three of the 19 adRP genes have been associated with incomplete
penetrance (PRPF31, PAP1, and RP1). To optimize mutational screening
procedures for such cases, a detailed case history including a family pedigree over
several generations is needed to recognize incomplete penetrance of the phenotype.
In cases where the pedigree suggests X-linked inheritance within the family, RPGR
and RP2 are the only candidates associated with RP so far. In addition, almost all
cases can be explained by mutations in either RPGR (up to 80% of the cases) or
RP2 (up to 20% of the cases) (Neidhardt et al., 2008; Roepman et al., 1996b;
Schwahn et al., 1998). A screening strategy starting with a mutation hot spot in
RPGR followed by sequencing of other exons has been shown to be successful in
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most cases and to reduce costs and efforts (Neidhardt et al., 2008). Additional loci on
the X-chromosome have been mapped, but the corresponding genes have not yet
been identified. Interestingly, RPGR mutations may also affect female carriers and
thus should not be associated with classical X-linked recessive inheritance. The
genetic basis for this observation is still unclear. Since skewed X-inactivation has not
been identified in affected female carriers so far, genetic or environmental modifiers
may be relevant too. In contrast to X-linked RP, the candidate selection is more
difficult in cases with autosomal recessive inheritance. Promising candidate genes for
arRP are PDE6alpha and PDE6beta that together explain about 5-10% of the cases
(Daiger et al., 2007). USH2A is a gene frequently found to be mutated in arRP (up to
20% of the cases), but is also associated with Usher Syndrome ((Hartong et al., 2006)
and references therein). Furthermore, ABCA4 and RPE65 often show RP-associated
mutations, but classically cause Stargardts disease or LCA (Figures 2, 3, 4 and 6,
Tables 2, 3 and 5). Thus, a thorough clinical characterization of the phenotype
including syndromic features will further facilitate the selection of candidate genes for
molecular genetic testing in a patient with arRP.
Following these screening strategies, the samples without identified mutations may
be included in research programs to identify novel loci and disease-associated genes.
Methods that are used to further characterize such samples often include array
technologies (SNP arrays) with the aim to identify linkage intervals in families with
multiple affected members or homozygous regions in the genome of consanguineous
families. Furthermore, array technologies may be used to directly screen for
mutations (Koenekoop et al., 2007).
In particular, genetic testing for the large gene ABCA4 and for all recessive or
dominant RP genes requires efficient diagnostic tests in order to examine the DNA
sample of a patient in an affordable amount of time. One such tool for mutation
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detection represent microarrays. This technique has been established for several
retinal diseases (Cremers et al., 2007; Jaakson et al., 2003; Zernant et al., 2005).
Also for CSNB, the large number of genes and mutations associated with this
disease are challenging for confirmation of the clinical diagnosis. Recently, a
microarray has been developed which provides a fast and rather inexpensive tool to
screen DNA samples from patients for known mutations in one of the above
mentioned genes (Zeitz et al., 2009). However, with this diagnostic test only known
sequence alterations can be detected as in the case of ABCA4 (Klevering et al.,
2004b). The most sensitive technology currently available for routine diagnostics is
direct DNA sequencing in combination with multiple ligation-dependent probe
amplification (MLPA), the latter of which can be used to reveal copy number
variations, such as deletions or duplications.
Another challenge for genetic testing is the interpretation of the results of these tests.
Many of the DNA sequence variations lead to amino acid substitutions and it is
difficult to predict the pathogenic effect for many of them. Therefore, functional
assays are needed to characterize these sequence alterations. For example, ABCA4
possesses an ATPase activity and it is possible to analyze specific missense
mutations in cell culture assays and answer the question of a potential pathogenic
effect (Sun et al., 2000). Due to the extensive individuality of pathogenic and nonpathogenic sequence alterations, this approach is difficult to realize in a routine
diagnostic setting. In addition, deep intronic mutations may be responsible for a
significant number of cases and these are extremely difficult to be analyzed in
functional assays.
Today, the new (next generation) sequencing technologies enable us to collect up to
500 million base pairs per single sequencing run at comparably low costs
(Voelkerding et al., 2009). This will complement or even replace other methods to
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identify mutations in genetically heterogeneous diseases, such as retinal
degenerations and dysfunctions.
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5.
Therapeutic approaches to retinal degenerations
The eye is ideally suited as a target organ for several different therapeutic
approaches as it is easy to access and enables to monitor the application of
therapeutics. It further allows a non-invasive follow up of therapeutic effects in vivo.
Its interconnected system of spatially well organized cell types facilitates the
application of therapeutics to the target cells. Moreover, the eye shows an efficient
blood-retinal barrier that greatly reduces or even prevents exchange of therapeutics
with other organs and thus may limit side effects and further therapy-provoked
immune responses like inflammation. In contrast to non-syndromic retinal diseases, it
will be difficult to treat extraocular symptoms in patients with a syndromic form of
retinal degeneration, e.g. Refsum disease, Joubert syndrome, Bardet Biedl syndrome,
or others.
Different avenues are currently followed in order to treat patients with retinal diseases.
These include the application of nutrition supplements or drugs, gene replacement
strategies, transplantation and stem cell technologies, as well as the implantation of
electric devices, known as retinal prosthesis.
We will discuss two therapeutic approaches that have advanced from successful
application in animal models to phase 1 and/or 2 clinical trials: One strategy involves
neurotrophic and survival factors that have been shown, for example in animal
models, to prolong the lifespan of affected retinal cells. The other one uses gene
replacement. Both showed a significant success rate for several inherited retinal
diseases.
The ciliary neurotrophic factor (CNTF) yielded promising results in two phase 2
studies. The therapeutic intervention, designated ´Encapsulated Cell Technology
(ECT, (Lanza et al., 1996))´, involves intraocular implants containing human cells,
which secrete CNTF (Emerich et al., 2008; Thanos et al., 2004). A therapeutic device,
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designated NT-501, was developed recently. Treatment of more than 120 patients
with RP revealed a positive biological effect in the retina and photoreceptors, as
measured by optical coherence tomography (OCT). However, the patients have been
monitored only for a relatively short period of time (12 months). Preliminary results of
these trials are encouraging but a long term follow-up is needed to evaluate the
success of treatment and possible adverse effects. A positive effect measured by
OCT has also been observed in patients with the dry form of AMD and geographic
atrophy who were treated with NT-501 implants. The wet form of AMD may also be
treated by delivering a structural antagonist of VEGF to the affected eye. Possible
application of encapsulated cell technology (ECT) in AMD treatment was recently
initiated (NT-503).
In therapeutic approaches that apply gene replacement technologies, viral vectors
have frequently been used to transduce retinal cells with intact copies of the mutated
gene. In most cases, either the recombinant adeno-associated virus (rAAV) or the
lentivirus provided the basis for the viral shuttle. Since cell specificity, expression
kinetics and packaging size differ significantly between these viruses, the selection of
the optimal virus type is essential for the therapeutic outcome. Furthermore,
combinations of different rAAV serotypes enable an even more controlled use of cell
specificity and expression kinetics (Auricchio et al., 2005; Neidhardt et al., 2005). For
example, the serotype rAAV2/4 is more specific to RPE than rAAV2/5, which
additionally transduces photoreceptors (Acland et al., 2005; Weber et al., 2003).
Their expression kinetics are similarly fast, while rAAV2/2-mediated expression is
significantly slower. An advantage of the lentivirus is to host larger genes of interest
than rAAV. It is specific to RPE cells after subretinal delivery (Tschernutter et al.,
2005).
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LCA patients with RPE65 mutations were the first to be treated successfully by gene
replacement therapies in three independent phase 1 clinical trials (Bainbridge et al.,
2008; Hauswirth et al., 2008; Maguire et al., 2008). These clinical trials have been
stimulated by encouraging results in a naturally occurring dog model of RPE65
mutations (Acland et al., 2001). It further seemed a promising target gene for
replacement therapy since the RPE65 deficiency results in visual impairment due to
depletion of visual pigment from the phototransduction cascade, but shows a high
degree of preservation of anatomical features within the retina. Furthermore, RPE65
is RPE specific and subretinal injection of viral shuttles can more efficiently transduce
RPE than photoreceptor cells, possibly because of anatomical barriers. Together with
the appropriate choice of rAAV serotypes for the transduction of RPE cells, the gene
therapy of RPE65 mutations resulted in increased retinal sensitivity in young adult
patients (Bainbridge et al., 2008; Hauswirth et al., 2008; Maguire et al., 2008). Some
patients had improved visual abilities in dim light conditions although the effect was
not detectable by ERG measurements. Importantly, significant side effects of the viral
treatment have not been detected so far. Future evaluations of long-term effects will
be needed to judge safety aspects and therapeutic potential of this first gene
replacement therapy in the eye.
In general, gene replacement is more feasible in patients with loss of function
mutations, represented by either recessive or dominant haploinsufficient alleles. In
contrast, dominant negative mutations require two steps of therapeutic intervention: (i)
inactivation or depletion of the dominant negative gene variant or gene product and
(ii) introduction and expression of the healthy gene copy. This two-step approach is
more challenging but several strategies to accomplish this are available (MillingtonWard et al., 1997). In addition, the discovery of RNA interference mechanism may
provide a suitable tool for the specific removal of transcripts encoding dominant
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negative protein species of a given gene. The development of current gene
replacement therapies focusses on genes that are frequently affected by recessive
mutations, including PDE, ABCA4, CNGB3, GNAT2, and AIPL1.
Future candidate genes for clinical trials will be selected on the basis of successful
treatment of an appropriate animal model, the frequency of the mutations found
within the respective gene, and the significance of the benefit expected for the patient.
Furthermore, it is well possible that existing therapies will be improved by gene
therapy approaches. The treatment of AMD often requires repeated injection of
rather expensive medications over years. Gene therapy could lead to a permanent
presence of AMD therapeutic agents in the eye, thus substituting repeated injections.
Moreover, one might speculate that drug-inducible expression systems will be
applied to control expression of the therapeutic protein in the eye. Such systems
would also be beneficiary to enable the adjustment of therapeutic concentrations
towards inter-individual phenotype differences.
In summary, gene therapy and the application of substances that prolong the lifespan
of affected retinal cells offer a multitude of possibilities that will contribute to the
treatment of retinal diseases and will help to slow down or even stop the progression
of several blinding eye diseases in the near future. For some of them, knowledge of
the disease causing mutation will be essential prior to a specific application. But for
others, a more general therapeutic approach, like treatment with neurotrophic or
antiapoptotic factors, will be possible without knowing the pathogenic gene variant.
However, we do not yet know or understand how a specific genotype contributes to
the therapeutic outcome. Therefore, genotyping of patients and a detailed
comparison of the genotype with the course of the therapeutic intervention will
provide important informations with regard to a combinatorial effect of DNA variants,
environmental factors, and the procedure of treatment.
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6.
Conclusions and outlook
The future in the field of retinal diseases will focus on the identification of additional
genes, the development of efficient and reliable diagnostic tests, and most
importantly on the development of treatment regimens.
Disease gene identification has become much more efficient with the availability of
the human genome sequence. What it needs today are comprehensive databases
integrating genetic but also clinical data in order to perform a detailed genotypephenotype comparison. This can reveal important information not only to diagnose a
disease in a patient or family for genetic counselling, but it may also have a predictive
value with respect to the likelihood of disease development and choices of therapy.
The recent progress in sequencing technology, including next and third generation
sequencing, will provide sequence information of entire introns in addition to exons. It
will further be feasible to sequence a complete set of genes with important functions
in retina, RPE, vitreous, but also other ocular structures. This will lead to the
identification of numerous DNA variations. The challenge is to discriminate between
the causative mutations, modifying alleles or other sequence variants, which confer a
risk or protection for the development of an ocular disease. To evaluate all these
variants, bioinformatic tools as well as sequence variation databases and clinical
data from patients are extremely important for the interpretation of the sequencing
results.
Current development of treatments is very encouraging and will improve the quality
of life of a patient. Nevertheless, years if not decades of work is ahead of us, which
will deliver important and exciting results in basic research and therapy.
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7.
References
1. Abd El-Aziz MM, Barragan I, O'Driscoll CA, Goodstadt L, Prigmore E, Borrego S, Mena M,
Pieras JI, El Ashry MF, Safieh LA, Shah A, Cheetham ME, Carter NP, Chakarova C, Ponting
CP, Bhattacharya SS, and Antinolo G (2008) EYS, encoding an ortholog of Drosophila
spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Nat Genet 40:1285-1287
2. Abid A, Ismail M, Mehdi SQ, and Khaliq S (2006) Identification of novel mutations in the
SEMA4A gene associated with retinal degenerative diseases. J Med Genet 43:378-381
3. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS,
Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, and Jacobson SG (2005)
Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to
the retina in a canine model of childhood blindness. Mol Ther 12:1072-1082
4. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE,
Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, and Bennett J (2001) Gene
therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92-95
5. al Jandal N, Farrar GJ, Kiang AS, Humphries MM, Bannon N, Findlay JB, Humphries P, and
Kenna PF (1999) A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal
dominant congenital stationary night blindness. Hum Mutat 13:75-81
6. Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L,
Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J,
Leppert M, Dean M, and Lupski JR (1997) A photoreceptor cell-specific ATP-binding
transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet
15:236-246
7. Alvarez Retuerto AI, Cantor RM, Gleeson JG, Ustaszewska A, Schackwitz WS, Pennacchio
LA, and Geschwind DH (2008) Association of common variants in the Joubert syndrome gene
(AHI1) with autism. Hum Mol Genet 17:3887-3896
8. Ambati J, Ambati BK, Yoo SH, Ianchulev S, and Adamis AP (2003) Age-Related Macular
Degeneration: Etiology, Pathogenesis, and Therapeutic Strategies. Surv Ophthalmol 48:257293
9. Andersen M, Christoffersen N, Sander B, Edmund C, Larsen M, Grau T, Wissinger B, Kohl S,
and Rosenberg T (2009) Oligocone trichromacy: Clinical and molecular genetic investigations.
Invest Ophthalmol Vis Sci
10. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers
ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL,
and Katsanis N (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl
syndrome. Nature 425:628-633
11. Apfelstedt-Sylla E, Theischen M, Ruther K, Wedemann H, Gal A, and Zrenner E (1995)
Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal
dominant retinal dystrophy and mutations in the human RDS/peripherin gene. Br J Ophthalmol
79:28-34
12. Audo I, Kohl S, Leroy BP, Munier FL, Guillonneau X, Mohand-Said S, Bujakowska K, Nandrot
EF, Lorenz B, Preising M, Kellner U, Renner AB, Bernd A, Antonio A, Moskova-Doumanova V,
Lancelot ME, Poloschek CM, Drumare I, Defoort-Dhellemmes S, Wissinger B, Leveillard T,
Hamel CP, Schorderet DF, De Baere E, Berger W, Jacobson SG, Zrenner E, Sahel JA,
Bhattacharya SS, and Zeitz C (2009) TRPM1 Is Mutated in Patients with AutosomalRecessive Complete Congenital Stationary Night Blindness. Am J Hum Genet 85:720-729
61
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
13. Augood CA, Vingerling JR, de Jong PT, Chakravarthy U, Seland J, Soubrane G, Tomazzoli L,
Topouzis F, Bentham G, Rahu M, Vioque J, Young IS, and Fletcher AE (2006) Prevalence of
age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Arch
Ophthalmol 124:529-535
14. Auricchio A and Rolling F (2005) Adeno-associated viral vectors for retinal gene transfer and
treatment of retinal diseases. Curr Gene Ther 5:339-348
15. Ayyagari R, Demirci FY, Liu J, Bingham EL, Stringham H, Kakuk LE, Boehnke M, Gorin MB,
Richards JE, and Sieving PA (2002) X-linked recessive atrophic macular degeneration from
RPGR mutation. Genomics 80:166-171
16. Azari AA, Aleman TS, Cideciyan AV, Schwartz SB, Windsor EA, Sumaroka A, Cheung AY,
Steinberg JD, Roman AJ, Stone EM, Sheffield VC, and Jacobson SG (2006) Retinal disease
expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide
degeneration. Invest Ophthalmol Vis Sci 47:5004-5010
17. Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, Ozilou C, Faivre L,
Laurent N, Foliguet B, Munnich A, Lyonnet S, Salomon R, Encha-Razavi F, Gubler MC,
Boddaert N, de Lonlay P, Johnson CA, Vekemans M, Antignac C, and Attie-Bitach T (2007)
The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum
Genet 80:186-194
18. Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, and Katsanis N (2003a) Identification
of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1
and BBS2. Am J Hum Genet 72:650-658
19. Badano JL, Kim JC, Hoskins BE, Lewis RA, Ansley SJ, Cutler DJ, Castellan C, Beales PL,
Leroux MR, and Katsanis N (2003b) Heterozygous mutations in BBS1, BBS2 and BBS6 have
a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.
Hum Mol Genet 12:1651-1659
20. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A,
Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke
FW, Carter BJ, Rubin GS, Moore AT, and Ali RR (2008) Effect of gene therapy on visual
function in Leber's congenital amaurosis. N Engl J Med 358:2231-2239
21. Baird PN, Chu D, Guida E, Vu HT, and Guymer R (2004) Association of the M55L and Q192R
paraoxonase gene polymorphisms with age-related macular degeneration. Am J Ophthalmol
138:665-666
22. Banerjee P, Kleyn PW, Knowles JA, Lewis CA, Ross BM, Parano E, Kovats SG, Lee JJ,
Penchaszadeh GK, Ott J, Jacobson SG, and Gilliam TC (1998) TULP1 mutation in two
extended Dominican kindreds with autosomal recessive retinitis pigmentosa. Nat Genet
18:177-179
23. Banin E, Mizrahi-Meissonnier L, Neis R, Silverstein S, Magyar I, Abeliovich D, Roepman R,
Berger W, Rosenberg T, and Sharon D (2007) A non-ancestral RPGR missense mutation in
families with either recessive or semi-dominant X-linked retinitis pigmentosa. Am J Med Genet
A 143A:1150-1158
24. Bareil C, Hamel CP, Delague V, Arnaud B, Demaille J, and Claustres M (2001) Segregation of
a mutation in CNGB1 encoding the beta-subunit of the rod cGMP-gated channel in a family
with autosomal recessive retinitis pigmentosa. Hum Genet 108:328-334
25. Bartoloni L, Blouin JL, Pan Y, Gehrig C, Maiti AK, Scamuffa N, Rossier C, Jorissen M,
Armengot M, Meeks M, Mitchison HM, Chung EM, DeLozier-Blanchet CD, Craigen WJ, and
Antonarakis SE (2002) Mutations in the DNAH11 (axonemal heavy chain dynein type 11)
gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proc
Natl Acad Sci U S A 99:10282-10286
62
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
26. Beales PL, Badano JL, Ross AJ, Ansley SJ, Hoskins BE, Kirsten B, Mein CA, Froguel P,
Scambler PJ, Lewis RA, Lupski JR, and Katsanis N (2003) Genetic interaction of BBS1
mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.
Am J Hum Genet 72:1187-1199
27. Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M,
Musarella MA, and Boycott KM (1998) Loss-of-function mutations in a calcium-channel
alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night
blindness. Nat Genet 19:264-267
28. Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AA,
Prinsen CF, Polomeno RC, Gal A, Drack AV, Musarella MA, Jacobson SG, Young RS, and
Weleber RG (2000) Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin,
cause X-linked complete congenital stationary night blindness. Nat Genet 26:319-323
29. Berger W (1998) Molecular dissection of Norrie disease. Acta Anat (Basel) 162:95-100
30. Berger W, Meindl A, van de Pol TJ, Cremers FP, Ropers HH, Doerner C, Monaco A, Bergen
AA, Lebo R, Warburg M, Zergollern L, Lorenz B, Gal A, Bleeker-Wagemakers EM, and
Meitinger T (1992a) Isolation of a candidate gene for Norrie disease by positional cloning. Nat
Genet 1:199-203
31. Berger W, v.d.Pol D, Bächner D, Oerlemans F, Winkens H, Hameister H, Wieringa B,
Hendriks W, and Ropers H-H (1996) An animal model for Norrie disease (ND): gene targeting
of the mouse ND gene. Hum Mol Genet 5:51-59
32. Berger W, van de Pol TJ, Warburg M, Gal A, Bleeker-Wagemakers L, de Silva H, Meindl A,
Meitinger T, Cremers F, and Ropers HH (1992b) Mutations in the candidate gene for Norrie
disease. Hum Mol Genet 1:461-465
33. Bernal S, Solans T, Gamundi MJ, Hernan I, de Jorge L, Carballo M, Navarro R, Tizzano E,
Ayuso C, and Baiget M (2008) Analysis of the involvement of the NR2E3 gene in autosomal
recessive retinal dystrophies. Clin Genet 73:360-366
34. Berson EL (1993) Retinitis pigmentosa. The Friedenwald Lecture. Invest Ophthalmol Vis Sci
34:1659-1676
35. Bessant DA, Payne AM, Mitton KP, Wang QL, Swain PK, Plant C, Bird AC, Zack DJ, Swaroop
A, and Bhattacharya SS (1999) A mutation in NRL is associated with autosomal dominant
retinitis pigmentosa. Nat Genet 21:355-356
36. Bhattacharya SS, Wright AF, Clayton JF, Price WH, Phillips CI, McKeown CM, Jay M, Bird AC,
Pearson PL, Southern EM, and . (1984) Close genetic linkage between X-linked retinitis
pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA
probe L1.28. Nature 309:253-255
37. Bhowmick R, Li M, Sun J, Baker SA, Insinna C, and Besharse JC (2009) Photoreceptor IFT
Complexes Containing Chaperones, Guanylyl Cyclase 1 and Rhodopsin. Traffic 10:648-663
38. Bhutto IA, McLeod DS, Hasegawa T, Kim SY, Merges C, Tong P, and Lutty GA (2006)
Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in
aged human choroid and eyes with age-related macular degeneration. Exp Eye Res 82:99110
39. Bird AC (2003) The Bowman lecture. Towards an understanding of age-related macular
disease. Eye 17:457-466
40. Black GC, Perveen R, Wiszniewski W, Dodd CL, Donnai D, and McLeod D (1999) A novel
hereditary developmental vitreoretinopathy with multiple ocular abnormalities localizing to a 5cM region of chromosome 5q13-q14. Ophthalmology 106:2074-2081
63
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
41. Boekhoorn SS, Isaacs A, Uitterlinden AG, van Duijn CM, Hofman A, de Jong PT, and
Vingerling JR (2008) Polymorphisms in the vascular endothelial growth factor gene and risk of
age-related macular degeneration: the Rotterdam Study. Ophthalmology 115:1899-1903
42. Bolz HJ (2009) [Genetics of Usher syndrome]. Ophthalmologe 106:496-504
43. Boonstra FN, Van Nouhuys CE, Schuil J, de Wijs IJ, van der Donk KP, Nikopoulos K,
Mukhopadhyay A, Scheffer H, Tilanus MA, Cremers FP, and Hoefsloot LH (2009) Clinical and
molecular evaluation of probands and family members with familial exudative vitreoretinopathy.
Invest Ophthalmol Vis Sci 50:4379-4385
44. Bowne SJ, Sullivan LS, Blanton SH, Cepko CL, Blackshaw S, Birch DG, Hughbanks-Wheaton
D, Heckenlively JR, and Daiger SP (2002) Mutations in the inosine monophosphate
dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis
pigmentosa. Hum Mol Genet 11:559-568
45. Brancati F, Barrano G, Silhavy JL, Marsh SE, Travaglini L, Bielas SL, Amorini M, Zablocka D,
Kayserili H, Al Gazali L, Bertini E, Boltshauser E, D'Hooghe M, Fazzi E, Fenerci EY,
Hennekam RC, Kiss A, Lees MM, Marco E, Phadke SR, Rigoli L, Romano S, Salpietro CD,
Sherr EH, Signorini S, Stromme P, Stuart B, Sztriha L, Viskochil DH, Yuksel A, Dallapiccola B,
Valente EM, and Gleeson JG (2007) CEP290 mutations are frequently identified in the oculorenal form of Joubert syndrome-related disorders. Am J Hum Genet 81:104-113
46. Brancati F, Travaglini L, Zablocka D, Boltshauser E, Accorsi P, Montagna G, Silhavy JL,
Barrano G, Bertini E, Emma F, Rigoli L, Dallapiccola B, Gleeson JG, and Valente EM (2008)
RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert
syndrome-related disorders. Clin Genet 74:164-170
47. Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, and Dryja TP (2001) Mutations in
ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.
Invest Ophthalmol Vis Sci 42:2229-2236
48. Brown DM, Graemiger RA, Hergersberg M, Schinzel A, Messmer EP, Niemeyer G,
Schneeberger SA, Streb LM, Taylor CM, Kimura AE, and . (1995) Genetic linkage of Wagner
disease and erosive vitreoretinopathy to chromosome 5q13-14. Arch Ophthalmol 113:671-675
49. Brown DM, Kimura AE, Weingeist TA, and Stone EM (1994) Erosive vitreoretinopathy. A new
clinical entity. Ophthalmology 101:694-704
50. Brunner S, Colman D, Travis AJ, Luhmann UF, Shi W, Feil S, Imsand C, Nelson J, Grimm C,
Rulicke T, Fundele R, Neidhardt J, and Berger W (2008) Overexpression of RPGR leads to
male infertility in mice due to defects in flagellar assembly. Biol Reprod 79:608-617
51. Brunner S, Skosyrski S, Kirschner-Schwabe R, Knobeloch KP, Neidhardt J, Feil S, Glaus E,
Luhmann UF, Ruether K, and Berger W (2009) Cone versus rod disease in a mutant Rpgr
mouse caused by different genetic backgrounds. Invest Ophthalmol Vis Sci 51:1106-1115
52. Cantagrel V, Silhavy JL, Bielas SL, Swistun D, Marsh SE, Bertrand JY, Audollent S, AttieBitach T, Holden KR, Dobyns WB, Traver D, Al Gazali L, Ali BR, Lindner TH, Caspary T, Otto
EA, Hildebrandt F, Glass IA, Logan CV, Johnson CA, Bennett C, Brancati F, Valente EM,
Woods CG, and Gleeson JG (2008) Mutations in the cilia gene ARL13B lead to the classical
form of Joubert syndrome. Am J Hum Genet 83:170-179
53. Caridi G, Murer L, Bellantuono R, Sorino P, Caringella DA, Gusmano R, and Ghiggeri GM
(1998) Renal-retinal syndromes: association of retinal anomalies and recessive
nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am J Kidney Dis
32:1059-1062
54. Chakarova CF, Hims MM, Bolz H, Abu-Safieh L, Patel RJ, Papaioannou MG, Inglehearn CF,
Keen TJ, Willis C, Moore AT, Rosenberg T, Webster AR, Bird AC, Gal A, Hunt D, Vithana EN,
64
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
and Bhattacharya SS (2002) Mutations in HPRP3, a third member of pre-mRNA splicing factor
genes, implicated in autosomal dominant retinitis pigmentosa. Hum Mol Genet 11:87-92
55. Chakarova CF, Papaioannou MG, Khanna H, Lopez I, Waseem N, Shah A, Theis T, Friedman
J, Maubaret C, Bujakowska K, Veraitch B, Abd El-Aziz MM, Prescott dQ, Parapuram SK,
Bickmore WA, Munro PM, Gal A, Hamel CP, Marigo V, Ponting CP, Wissinger B, Zrenner E,
Matter K, Swaroop A, Koenekoop RK, and Bhattacharya SS (2007) Mutations in TOPORS
cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium
atrophy. Am J Hum Genet 81:1098-1103
56. Chamberlain M, Baird P, Dirani M, and Guymer R (2006) Unraveling a complex genetic
disease: age-related macular degeneration. Surv Ophthalmol 51:576-586
57. Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H,
Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively J, and Wissinger B (2009) A
homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to
mutations in the PDE6C gene. Proc Natl Acad Sci U S A 106:19581-19586
58. Chen ZY, Battinelli EM, Fielder A, Bundey S, Sims K, Breakefield XO, and Craig IW (1993) A
mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative
vitreoretinopathy. Nat Genet 5:180-183
59. Chen ZY, Hendriks RW, Jobling MA, Powell JF, Breakefield XO, Sims KB, and Craig IW (1992)
Isolation and characterization of a candidate gene for Norrie disease. Nat Genet 1:204-208
60. Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz TE, Swiderski RE, Nishimura DY, Braun TA,
Kim KY, Huang J, Elbedour K, Carmi R, Slusarski DC, Casavant TL, Stone EM, and Sheffield
VC (2006) Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase,
as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci U S A 103:6287-6292
61. Churchill AJ, Carter JG, Lovell HC, Ramsden C, Turner SJ, Yeung A, Escardo J, and Atan D
(2006) VEGF polymorphisms are associated with neovascular age-related macular
degeneration. Hum Mol Genet 15:2955-2961
62. Coene KL, Roepman R, Doherty D, Afroze B, Kroes HY, Letteboer SJ, Ngu LH, Budny B, Van
Wijk E, Gorden NT, Azhimi M, Thauvin-Robinet C, Veltman JA, Boink M, Kleefstra T, Cremers
FP, van Bokhoven H, and de Brouwer AP (2009) OFD1 is mutated in X-linked Joubert
syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet 85:465-481
63. Collin GB, Cyr E, Bronson R, Marshall JD, Gifford EJ, Hicks W, Murray SA, Zheng QY, Smith
RS, Nishina PM, and Naggert JK (2005) Alms1-disrupted mice recapitulate human Alstrom
syndrome. Hum Mol Genet 14:2323-2333
64. Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P, Beck S, Boerkoel CF,
Sicolo N, Martin M, Nishina PM, and Naggert JK (2002) Mutations in ALMS1 cause obesity,
type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 31:74-78
65. Collin RW, Littink KW, Klevering BJ, van den Born LI, Koenekoop RK, Zonneveld MN,
Blokland EA, Strom TM, Hoyng CB, den Hollander AI, and Cremers FP (2008) Identification of
a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with
retinitis pigmentosa. Am J Hum Genet 83:594-603
66. Colliton RP, Bason L, Lu FM, Piccoli DA, Krantz ID, and Spinner NB (2001) Mutation analysis
of Jagged1 (JAG1) in Alagille syndrome patients. Hum Mutat 17:151-152
67. Conley YP, Thalamuthu A, Jakobsdottir J, Weeks DE, Mah T, Ferrell RE, and Gorin MB (2005)
Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the
complement system in the etiology of age-related maculopathy. Hum Mol Genet 14:1991-2002
68. Coppieters F, Leroy BP, Beysen D, Hellemans J, De Bosscher K, Haegeman G, Robberecht K,
Wuyts W, Coucke PJ, and De Baere E (2007) Recurrent mutation in the first zinc finger of the
65
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa. Am J Hum
Genet 81:147-157
69. Corbit KC, Shyer AE, Dowdle WE, Gaulden J, Singla V, Chen MH, Chuang PT, and Reiter JF
(2008) Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and nonciliary mechanisms. Nat Cell Biol 10:70-76
70. Cremers FP, Armstrong SA, Seabra MC, Brown MS, and Goldstein JL (1994) REP-2, a Rab
escort protein encoded by the choroideremia-like gene. J Biol Chem 269:2111-2117
71. Cremers FP, Kimberling WJ, Kulm M, de Brouwer AP, Van Wijk E, Te BH, Cremers CW,
Hoefsloot LH, Banfi S, Simonelli F, Fleischhauer JC, Berger W, Kelley PM, Haralambous E,
Bitner-Glindzicz M, Webster AR, Saihan Z, De Baere E, Leroy BP, Silvestri G, McKay GJ,
Koenekoop RK, Millan JM, Rosenberg T, Joensuu T, Sankila EM, Weil D, Weston MD,
Wissinger B, and Kremer H (2007) Development of a genotyping microarray for Usher
syndrome. J Med Genet 44:153-160
72. Cremers FP, van de Pol DJ, van Driel M, den Hollander AI, van Haren FJ, Knoers NV, Tijmes
N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Deutman AF, and Hoyng CB
(1998) Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site
mutations in the Stargardt's disease gene ABCR. Hum Mol Genet 7:355-362
73. Cremers FP, van de Pol DJ, van Kerkhoff LP, Wieringa B, and Ropers HH (1990) Cloning of a
gene that is rearranged in patients with choroideraemia. Nature 347:674-677
74. Daiger SP, Bowne SJ, and Sullivan LS (2007) Perspective on genes and mutations causing
retinitis pigmentosa. Arch Ophthalmol 125:151-158
75. Davidson AE, Millar ID, Urquhart JE, Burgess-Mullan R, Shweikh Y, Parry N, O'Sullivan J,
Maher GJ, McKibbin M, Downes SM, Lotery AJ, Jacobson SG, Brown PD, Black GC, and
Manson FD (2009) Missense mutations in a retinal pigment epithelium protein, bestrophin-1,
cause retinitis pigmentosa. Am J Hum Genet 85:581-592
76. Davis RE, Swiderski RE, Rahmouni K, Nishimura DY, Mullins RF, Agassandian K, Philp AR,
Searby CC, Andrews MP, Thompson S, Berry CJ, Thedens DR, Yang B, Weiss RM, Cassell
MD, Stone EM, and Sheffield VC (2007) A knockin mouse model of the Bardet-Biedl
syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity.
Proc Natl Acad Sci U S A 104:19422-19427
77. Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL, Blair-Reid S, Sriram N,
Katsanis N, Attie-Bitach T, Afford SC, Copp AJ, Kelly DA, Gull K, and Johnson CA (2007) The
Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary
cilium formation. Hum Mol Genet 16:173-186
78. Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K, Golzio C, Lacoste T, Besse L,
Ozilou C, Moutkine I, Hellman NE, Anselme I, Silbermann F, Vesque C, Gerhardt C,
Rattenberry E, Wolf MT, Gubler MC, Martinovic J, Encha-Razavi F, Boddaert N, Gonzales M,
Macher MA, Nivet H, Champion G, Bertheleme JP, Niaudet P, McDonald F, Hildebrandt F,
Johnson CA, Vekemans M, Antignac C, Ruther U, Schneider-Maunoury S, Attie-Bitach T, and
Saunier S (2007) The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome
(Joubert syndrome type B) and Meckel syndrome. Nat Genet 39:875-881
79. Demirci FY, Rigatti BW, Wen G, Radak AL, Mah TS, Baic CL, Traboulsi EI, Alitalo T, Ramser
J, and Gorin MB (2002) X-linked cone-rod dystrophy (locus COD1): identification of mutations
in RPGR exon ORF15. Am J Hum Genet 70:1049-1053
80. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN,
Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, and
Cremers FP (2006) Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber
congenital amaurosis. Am J Hum Genet 79:556-561
66
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
81. den Hollander AI, Roepman R, Koenekoop RK, and Cremers FP (2008) Leber congenital
amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27:391-419
82. den Hollander AI, ten Brink JB, de Kok YJ, van Soest S, van den Born LI, van Driel MA, van
de Pol DJ, Payne AM, Bhattacharya SS, Kellner U, Hoyng CB, Westerveld A, Brunner HG,
Bleeker-Wagemakers EM, Deutman AF, Heckenlively JR, Cremers FP, and Bergen AA (1999)
Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).
Nat Genet 23:217-221
83. Dewan A, Liu MG, Hartman S, Zhang SSM, Liu DTL, Zhao C, Tam POS, Chan WM, Lam DSC,
Snyder M, Barnstable C, Pang CP, and Hoh J (2006) HTRA1 promoter polymorphism in wet
age-related macular degeneration. Science 314:989-992
84. Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al Gazali L, Al Tawari
AA, Kayserili H, Sztriha L, and Gleeson JG (2004) Mutations in the AHI1 gene, encoding
jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 75:979-987
85. Donoso LA, Edwards AO, Frost AT, Ritter R, III, Ahmad N, Vrabec T, Rogers J, Meyer D, and
Parma S (2003) Clinical variability of Stickler syndrome: role of exon 2 of the collagen
COL2A1 gene. Surv Ophthalmol 48:191-203
86. Donoso LA, Kim D, Frost A, Callahan A, and Hageman G (2006) The role of inflammation in
the pathogenesis of age-related macular degeneration. Surv Ophthalmol 51:137-152
87. Dryja TP, Berson EL, Rao VR, and Oprian DD (1993) Heterozygous missense mutation in the
rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet 4:280-283
88. Dryja TP, Finn JT, Peng YW, McGee TL, Berson EL, and Yau KW (1995) Mutations in the
gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive
retinitis pigmentosa. Proc Natl Acad Sci U S A 92:10177-10181
89. Dryja TP, Hahn LB, Reboul T, and Arnaud B (1996) Missense mutation in the gene encoding
the alpha subunit of rod transducin in the Nougaret form of congenital stationary night
blindness. Nat Genet 13:358-360
90. Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, Derlacki DJ, and
Rajagopalan AS (2005) Night blindness and abnormal cone electroretinogram ON responses
in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci U S A
102:4884-4889
91. Dryja TP, McGee TL, Hahn LB, Cowley GS, Olsson JE, Reichel E, Sandberg MA, and Berson
EL (1990) Mutations within the rhodopsin gene in patients with autosomal dominant retinitis
pigmentosa. N Engl J Med 323:1302-1307
92. Edvardson S, Shaag A, Zenvirt S, Erlich Y, Hannon GJ, Shanske AL, Gomori JM, Ekstein J,
and Elpeleg O (2010) Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a
TMEM216 mutation. Am J Hum Genet 86:93-97
93. Edwards AO, Chen D, Fridley BL, James KM, Wu Y, Abecasis G, Swaroop A, Othman M,
Branham K, Iyengar SK, Sivakumaran TA, Klein R, Klein BE, and Tosakulwong N (2008) Tolllike receptor polymorphisms and age-related macular degeneration. Invest Ophthalmol Vis Sci
49:1652-1659
94. Edwards AO and Malek G (2007) Molecular genetics of AMD and current animal models.
Angiogenesis 10:119-132
95. Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, and Farrer LA (2005) Complement
factor H polymorphism and age-related macular degeneration. Science 308:421-424
96. Emerich DF and Thanos CG (2008) NT-501: an ophthalmic implant of polymer-encapsulated
ciliary neurotrophic factor-producing cells. Curr Opin Mol Ther 10:506-515
67
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
97. Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, Jones S, Collins A, Stone E, and
Lotery A (2008) Association between the SERPING1 gene and age-related macular
degeneration: a two-stage case-control study. Lancet 372:1828-1834
98. Escudier E, Duquesnoy P, Papon JF, and Amselem S (2009) Ciliary defects and genetics of
primary ciliary dyskinesia. Paediatr Respir Rev 10:51-54
99. Eudy JD, Weston MD, Yao S, Hoover DM, Rehm HL, Ma-Edmonds M, Yan D, Ahmad I,
Cheng JJ, Ayuso C, Cremers C, Davenport S, Moller C, Talmadge CB, Beisel KW, Tamayo M,
Morton CC, Swaroop A, Kimberling WJ, and Sumegi J (1998) Mutation of a gene encoding a
protein with extracellular matrix motifs in Usher syndrome type IIa. Science 280:1753-1757
100. Failly M, Saitta A, Munoz A, Falconnet E, Rossier C, Santamaria F, de Santi MM, Lazor R,
DeLozier-Blanchet CD, Bartoloni L, and Blouin JL (2008) DNAI1 mutations explain only 2% of
primary ciliary dykinesia. Respiration 76:198-204
101. Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL,
May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL,
Beales PL, Katsanis N, Davidson WS, and Leroux MR (2004) Mutations in a member of the
Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet
36:989-993
102. Farrar GJ, Kenna P, Jordan SA, Kumar-Singh R, Humphries MM, Sharp EM, Sheils DM, and
Humphries P (1991) A three-base-pair deletion in the peripherin-RDS gene in one form of
retinitis pigmentosa. Nature 354:478-480
103. Faustino NA and Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev
17:419-437
104. Felbor U, Schilling H, and Weber BH (1997) Adult vitelliform macular dystrophy is frequently
associated with mutations in the peripherin/RDS gene. Hum Mutat 10:301-309
105. Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al Nouri D, Al Rumayyan A, Topcu M,
Gascon G, Bodell A, Shugart YY, Ruvolo M, and Walsh CA (2004) Abnormal cerebellar
development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat
Genet 36:1008-1013
106. Fishman GA, Stone EM, Eliason DA, Taylor CM, Lindeman M, and Derlacki DJ (2003) ABCA4
gene sequence variations in patients with autosomal recessive cone-rod dystrophy. Arch
Ophthalmol 121:851-855
107. Fliegauf M, Horvath J, von Schnakenburg C, Olbrich H, Muller D, Thumfart J, Schermer B,
Pazour GJ, Neumann HP, Zentgraf H, Benzing T, and Omran H (2006) Nephrocystin
specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor
connecting cilia. J Am Soc Nephrol 17:2424-2433
108. Freund CL, Gregory-Evans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, Bellingham
J, Ng D, Herbrick JA, Duncan A, Scherer SW, Tsui LC, Loutradis-Anagnostou A, Jacobson
SG, Cepko CL, Bhattacharya SS, and McInnes RR (1997) Cone-rod dystrophy due to
mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance
of the photoreceptor. Cell 91:543-553
109. Friedman JS, Ray JW, Waseem N, Johnson K, Brooks MJ, Hugosson T, Breuer D, Branham
KE, Krauth DS, Bowne SJ, Sullivan LS, Ponjavic V, Granse L, Khanna R, Trager EH, Gieser
LM, Hughbanks-Wheaton D, Cojocaru RI, Ghiasvand NM, Chakarova CF, Abrahamson M,
Goring HH, Webster AR, Birch DG, Abecasis GR, Fann Y, Bhattacharya SS, Daiger SP,
Heckenlively JR, Andreasson S, and Swaroop A (2009) Mutations in a BTB-Kelch protein,
KLHL7, cause autosomal-dominant retinitis pigmentosa. Am J Hum Genet 84:792-800
68
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
110. Fritchie K, Siintola E, Armao D, Lehesjoki AE, Marino T, Powell C, Tennison M, Booker JM,
Koch S, Partanen S, Suzuki K, Tyynela J, and Thorne LB (2009) Novel mutation and the first
prenatal screening of cathepsin D deficiency (CLN10). Acta Neuropathol 117:201-208
111. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, and Weber BH
(2008) Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715)
mRNA. Nat Genet 40:892-896
112. Fruttiger M (2007) Development of the retinal vasculature. Angiogenesis 10:77-88
113. Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, and Gal A (1995) A homozygous 1-base
pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nat
Genet 10:360-362
114. Fuchs S, van de Pol DJ, Beudt U, Kellner U, Meire F, Berger W, and Gal A (1996) Three novel
and two recurrent mutations of the Norrie disease gene in patients with Norrie syndrome. Hum
Mutat 8:85-88
115. Fuentes JJ, Volpini V, Fernandez-Toral F, Coto E, and Estivill X (1993) Identification of two
new missense mutations (K58N and R121Q) in the Norrie disease (ND) gene in two Spanish
families. Hum Mol Genet 2:1953-1955
116. Furuki S, Tamura S, Matsumoto N, Miyata N, Moser A, Moser HW, and Fujiki Y (2006)
Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders of
complementation group 8 impair its stability, peroxisomal localization, and interaction with the
Pex1p x Pex6p complex. J Biol Chem 281:1317-1323
117. Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, and Vollrath D
(2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene,
cause retinitis pigmentosa. Nat Genet 26:270-271
118. Gal A, Orth U, Baehr W, Schwinger E, and Rosenberg T (1994) Heterozygous missense
mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant
stationary night blindness. Nat Genet 7:64-68
119. Gao H, Boustany RM, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, Gillis T, Qin X, Liu S,
Donahue LR, Bronson RT, Faust JR, Stout D, Haines JL, Lerner TJ, and MacDonald ME
(2002) Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal
ceroid lipofuscinosis in man and mouse. Am J Hum Genet 70:324-335
120. Geisbrecht BV, Collins CS, Reuber BE, and Gould SJ (1998) Disruption of a PEX1-PEX6
interaction is the most common cause of the neurologic disorders Zellweger syndrome,
neonatal adrenoleukodystrophy, and infantile Refsum disease. Proc Natl Acad Sci U S A
95:8630-8635
121. Geller AM and Sieving PA (1993) Assessment of foveal cone photoreceptors in Stargardt's
macular dystrophy using a small dot detection task. Vision Res 33:1509-1524
122. Gerdes JM, Liu Y, Zaghloul NA, Leitch CC, Lawson SS, Kato M, Beachy PA, Beales PL,
DeMartino GN, Fisher S, Badano JL, and Katsanis N (2007) Disruption of the basal body
compromises proteasomal function and perturbs intracellular Wnt response. Nat Genet
39:1350-1360
123. Gerth C, Zawadzki RJ, Werner JS, and Heon E (2008) Retinal morphology in patients with
BBS1 and BBS10 related Bardet-Biedl Syndrome evaluated by Fourier-domain optical
coherence tomography. Vision Res 48:392-399
124. Giannakis E, Jokiranta TS, Male DA, Ranganathan S, Ormsby RJ, Fischetti VA, Mold C, and
Gordon DL (2003) A common site within factor H SCR 7 responsible for binding heparin, Creactive protein and streptococcal M protein. Eur J Immunol 33:962-969
69
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
125. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J,
Barile GR, Smith RT, Dean M, and Allikmets R (2006) Variation in factor B (BF) and
complement component 2 (C2) genes is associated with age-related macular degeneration.
Nat Genet 38:458-462
126. Gorden NT, Arts HH, Parisi MA, Coene KL, Letteboer SJ, van Beersum SE, Mans DA, Hikida
A, Eckert M, Knutzen D, Alswaid AF, Ozyurek H, Dibooglu S, Otto EA, Liu Y, Davis EE, Hutter
CM, Bammler TK, Farin FM, Dorschner M, Topcu M, Zackai EH, Rosenthal P, Owens KN,
Katsanis N, Vincent JB, Hildebrandt F, Rubel EW, Raible DW, Knoers NV, Chance PF,
Roepman R, Moens CB, Glass IA, and Doherty D (2008) CC2D2A is mutated in Joubert
syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum
Genet 83:559-571
127. Gotoh N, Yamada R, Hiratani H, Renault V, Kuroiwa S, Monet M, Toyoda S, Chida S, Mandai
M, Otani A, Yoshimura N, and Matsuda F (2006) No association between complement factor
H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum
Genet 120:139-143
128. Grisanti S and Tatar O (2008) The role of vascular endothelial growth factor and other
endogenous interplayers in age-related macular degeneration. Prog Retin Eye Res 27:372390
129. Guichard C, Harricane MC, Lafitte JJ, Godard P, Zaegel M, Tack V, Lalau G, and Bouvagnet
P (2001) Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus
and primary ciliary dyskinesia (Kartagener syndrome). Am J Hum Genet 68:1030-1035
130. Gupta SK, Leonard BC, Damji KF, and Bulman DE (2002) A frame shift mutation in a tissuespecific alternatively spliced exon of collagen 2A1 in Wagner's vitreoretinal degeneration. Am
J Ophthalmol 133:203-210
131. Haddad S, Chen CA, Santangelo SL, and Seddon JM (2006) The genetics of age-related
macular degeneration: A review of progress to date. Surv Ophthalmol 51:316-363
132. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL,
Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC,
Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J,
Zernant J, Merriam JE, Gold B, Dean M, and Allikmets R (2005) A common haplotype in the
complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related
macular degeneration. Proc Natl Acad Sci U S A 102:7227-7232
133. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, and Mullins RF (2001)
An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes
at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog
Retin Eye Res 20:705-732
134. Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, Beck G, Hockey R,
Hanna DB, Gorman S, Duhl D, Carmi R, Bennett J, Weleber RG, Fishman GA, Wright AF,
Stone EM, and Sheffield VC (2000) Mutation of a nuclear receptor gene, NR2E3, causes
enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet 24:127-131
135. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY,
Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, and Pericak-Vance MA
(2005) Complement factor H variant increases the risk of age-related macular degeneration.
Science 308:419-421
136. Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agarwal A, Postel EA, Olson L, Kenealy
SJ, Hauser M, Gilbert JR, and Pericak-Vance MA (2006) Functional candidate genes in agerelated macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest
Ophthalmol Vis Sci 47:329-335
137. Hamel C (2006) Retinitis pigmentosa. Orphanet J Rare Dis 1:4070
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
138. Hartong DT, Berson EL, and Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795-1809
139. Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ,
Boye SL, Flotte TR, Byrne BJ, and Jacobson SG (2008) Treatment of leber congenital
amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus
gene vector: short-term results of a phase I trial. Hum Gene Ther 19:979-990
140. He X (2008) Cilia put a brake on Wnt signalling. Nat Cell Biol 10:11-13
141. Hearn T, Renforth GL, Spalluto C, Hanley NA, Piper K, Brickwood S, White C, Connolly V,
Taylor JF, Russell-Eggitt I, Bonneau D, Walker M, and Wilson DI (2002) Mutation of ALMS1, a
large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat
Genet 31:79-83
142. Heine C, Koch B, Storch S, Kohlschutter A, Palmer DN, and Braulke T (2004) Defective
endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal degradation of
endocytosed arylsulfatase A. J Biol Chem 279:22347-22352
143. Hejtmancik JF, Jiao X, Li A, Sergeev YV, Ding X, Sharma AK, Chan CC, Medina I, and
Edwards AO (2008) Mutations in KCNJ13 cause autosomal-dominant snowflake vitreoretinal
degeneration. Am J Hum Genet 82:174-180
144. Heon E, Westall C, Carmi R, Elbedour K, Panton C, Mackeen L, Stone EM, and Sheffield VC
(2005) Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome. Am J Med
Genet A 132A:283-287
145. Hildebrandt F, Attanasio M, and Otto E (2009) Nephronophthisis: disease mechanisms of a
ciliopathy. J Am Soc Nephrol 20:23-35
146. Hirose T, Lee KY, and Schepens CL (1974) Snowflake degeneration in hereditary vitreoretinal
degeneration. Am J Ophthalmol 77:143-153
147. Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG,
and Perez VL (2008) Oxidative damage-induced inflammation initiates age-related macular
degeneration. Nat Med 14:194-198
148. Holmberg V, Jalanko A, Isosomppi J, Fabritius AL, Peltonen L, and Kopra O (2004) The
mouse ortholog of the neuronal ceroid lipofuscinosis CLN5 gene encodes a soluble lysosomal
glycoprotein expressed in the developing brain. Neurobiol Dis 16:29-40
149. Hong DH and Li T (2002) Complex expression pattern of RPGR reveals a role for purine-rich
exonic splicing enhancers. Invest Ophthalmol Vis Sci 43:3373-3382
150. Hsieh M, Boerboom D, Shimada M, Lo Y, Parlow AF, Luhmann UF, Berger W, and Richards
JS (2005) Mice null for Frizzled4 (Fzd4-/-) are infertile and exhibit impaired corpora lutea
formation and function. Biol Reprod 73:1135-1146
151. Huang SH, Pittler SJ, Huang X, Oliveira L, Berson EL, and Dryja TP (1995) Autosomal
recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP
phosphodiesterase. Nat Genet 11:468-471
152. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, and Chakravarthy U (2006) A
common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of
age-related macular degeneration. Nat Genet 38:1173-1177
153. Iannaccone A, Breuer DK, Wang XF, Kuo SF, Normando EM, Filippova E, Baldi A, Hiriyanna
S, MacDonald CB, Baldi F, Cosgrove D, Morton CC, Swaroop A, and Jablonski MM (2003)
Clinical and immunohistochemical evidence for an X linked retinitis pigmentosa syndrome with
recurrent infections and hearing loss in association with an RPGR mutation. J Med Genet
40:e118-
71
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
154. Ibanez-Tallon I, Gorokhova S, and Heintz N (2002) Loss of function of axonemal dynein
Mdnah5 causes primary ciliary dyskinesia and hydrocephalus. Hum Mol Genet 11:715-721
155. Ikeda T, Obayashi H, Hasegawa G, Nakamura N, Yoshikawa T, Imamura Y, Koizumi K, and
Kinoshita S (2001) Paraoxonase gene polymorphisms and plasma oxidized low-density
lipoprotein level as possible risk factors for exudative age-related macular degeneration. Am J
Ophthalmol 132:191-195
156. International Batten Disease Consortium (1995) Isolation of a novel gene underlying Batten
disease, CLN3. The International Batten Disease Consortium. Cell 82:949-957
157. Isosomppi J, Vesa J, Jalanko A, and Peltonen L (2002) Lysosomal localization of the neuronal
ceroid lipofuscinosis CLN5 protein. Hum Mol Genet 11:885-891
158. Ivings L, Towns KV, Matin MA, Taylor C, Ponchel F, Grainger RJ, Ramesar RS, Mackey DA,
and Inglehearn CF (2008) Evaluation of splicing efficiency in lymphoblastoid cell lines from
patients with splicing-factor retinitis pigmentosa. Mol Vis 14:2357-2366
159. Jaakson K, Zernant J, Kulm M, Hutchinson A, Tonisson N, Glavac D, Ravnik-Glavac M,
Hawlina M, Meltzer MR, Caruso RC, Testa F, Maugeri A, Hoyng CB, Gouras P, Simonelli F,
Lewis RA, Lupski JR, Cremers FP, and Allikmets R (2003) Genotyping microarray (gene chip)
for the ABCR (ABCA4) gene. Hum Mutat 22:395-403
160. Jacobson SG, Sumaroka A, Aleman TS, Cideciyan AV, Schwartz SB, Roman AJ, McInnes RR,
Sheffield VC, Stone EM, Swaroop A, and Wright AF (2004) Nuclear receptor NR2E3 gene
mutations distort human retinal laminar architecture and cause an unusual degeneration. Hum
Mol Genet 13:1893-1902
161. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, and Gorin MB (2005)
Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet
77:389-407
162. Jansen GA, Waterham HR, and Wanders RJ (2004) Molecular basis of Refsum disease:
sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7).
Hum Mutat 23:209-218
163. Jarvela I, Sainio M, Rantamaki T, Olkkonen VM, Carpen O, Peltonen L, and Jalanko A (1998)
Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Hum
Mol Genet 7:85-90
164. Javitt JC, Zhou Z, Maguire MG, Fine SL, and Willke RJ (2003) Incidence of exudative agerelated macular degeneration among elderly Americans. Ophthalmology 110:1534-1539
165. Jiang ST, Chiou YY, Wang E, Chien YL, Ho HH, Tsai FJ, Lin CY, Tsai SP, and Li H (2009)
Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse. Hum Mol
Genet 18:1566-1577
166. Jiao X, Ventruto V, Trese MT, Shastry BS, and Hejtmancik JF (2004) Autosomal recessive
familial exudative vitreoretinopathy is associated with mutations in LRP5. Am J Hum Genet
75:878-884
167. Junge HJ, Yang S, Burton JB, Paes K, Shu X, French DM, Costa M, Rice DS, and Ye W
(2009) TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wntinduced FZD4/beta-catenin signaling. Cell 139:299-311
168. Kajiwara K, Berson EL, and Dryja TP (1994) Digenic retinitis pigmentosa due to mutations at
the unlinked peripherin/RDS and ROM1 loci. Science 264:1604-1608
169. Kajiwara K, Hahn LB, Mukai S, Travis GH, Berson EL, and Dryja TP (1991) Mutations in the
human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature
354:480-483
72
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
170. Katsanis N (2004) The oligogenic properties of Bardet-Biedl syndrome. Hum Mol Genet 13
Spec No 1:R65-R71
171. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ,
Davidson WS, Beales PL, and Lupski JR (2001a) Triallelic inheritance in Bardet-Biedl
syndrome, a Mendelian recessive disorder. Science 293:2256-2259
172. Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS, Parfrey PS, Ansley SJ, Davidson
WS, and Lupski JR (2000) Mutations in MKKS cause obesity, retinal dystrophy and renal
malformations associated with Bardet-Biedl syndrome. Nat Genet 26:67-70
173. Katsanis N, Lupski JR, and Beales PL (2001b) Exploring the molecular basis of Bardet-Biedl
syndrome. Hum Mol Genet 10:2293-2299
174. Kaufmann SJ, Goldberg MF, Orth DH, Fishman GA, Tessler H, and Mizuno K (1982)
Autosomal dominant vitreoretinochoroidopathy. Arch Ophthalmol 272-278
175. Keen TJ, Hims MM, McKie AB, Moore AT, Doran RM, Mackey DA, Mansfield DC, Mueller RF,
Bhattacharya SS, Bird AC, Markham AF, and Inglehearn CF (2002) Mutations in a protein
target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis
pigmentosa. Eur J Hum Genet 10:245-249
176. Keen TJ, Inglehearn CF, Kim R, Bird AC, and Bhattacharya S (1994) Retinal pattern
dystrophy associated with a 4 bp insertion at codon 140 in the RDS-peripherin gene. Hum Mol
Genet 3:367-368
177. Kellner U, Fuchs S, Bornfeld N, Foerster MH, and Gal A (1996) Ocular phenotypes associated
with two mutations (R121W, C126X) in the Norrie disease gene. Ophthalmic Genet 17:67-74
178. Kennan A, Aherne A, and Humphries P (2005) Light in retinitis pigmentosa. Trends Genet
21:103-110
179. Kennan A, Aherne A, Palfi A, Humphries M, McKee A, Stitt A, Simpson DA, Demtroder K,
Orntoft T, Ayuso C, Kenna PF, Farrar GJ, and Humphries P (2002) Identification of an
IMPDH1 mutation in autosomal dominant retinitis pigmentosa (RP10) revealed following
comparative microarray analysis of transcripts derived from retinas of wild-type and Rho(-/-)
mice. Hum Mol Genet 11:547-557
180. Khanna H, Hurd TW, Lillo C, Shu X, Parapuram SK, He S, Akimoto M, Wright AF, Margolis B,
Williams DS, and Swaroop A (2005) RPGR-ORF15, which is mutated in retinitis pigmentosa,
associates with SMC1, SMC3, and microtubule transport proteins. J Biol Chem 280:3358033587
181. Kim BJ and Fulton AB (2007) The genetics and ocular findings of Alagille syndrome. Semin
Ophthalmol 22:205-210
182. Kim IK, Ji F, Morrison MA, Adams S, Zhang Q, Lane AM, Capone A, Dryja TP, Ott J, Miller JW,
and DeAngelis MM (2008) Comprehensive analysis of CRP, CFH Y402H and environmental
risk factors on risk of neovascular age-related macular degeneration. Mol Vis 14:1487-1495
183. Kirschner R, Erturk D, Zeitz C, Sahin S, Ramser J, Cremers FP, Ropers HH, and Berger W
(2001) DNA sequence comparison of human and mouse retinitis pigmentosa GTPase
regulator (RPGR) identifies tissue-specific exons and putative regulatory elements. Hum
Genet 109:271-278
184. Kirschner R, Rosenberg T, Schultz-Heienbrok R, Lenzner S, Feil S, Roepman R, Cremers FP,
Ropers HH, and Berger W (1999) RPGR transcription studies in mouse and human tissues
reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa.
Hum Mol Genet 8:1571-1578
73
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
185. Kitiratschky VB, Grau T, Bernd A, Zrenner E, Jagle H, Renner AB, Kellner U, Rudolph G,
Jacobson SG, Cideciyan AV, Schaich S, Kohl S, and Wissinger B (2008) ABCA4 gene
analysis in patients with autosomal recessive cone and cone rod dystrophies. Eur J Hum
Genet 16:812-819
186. Klaver CC, Assink JJ, van Leeuwen R, Wolfs RC, Vingerling JR, Stijnen T, Hofman A, and de
Jong PT (2001) Incidence and progression rates of age-related maculopathy: the Rotterdam
Study. Invest Ophthalmol Vis Sci 42:2237-2241
187. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP,
Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, and Hoh J (2005)
Complement factor H polymorphism in age-related macular degeneration. Science 308:385389
188. Klevering BJ, Maugeri A, Wagner A, Go SL, Vink C, Cremers FP, and Hoyng CB (2004a)
Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or
retinitis pigmentosa. Ophthalmology 111:546-553
189. Klevering BJ, Yzer S, Rohrschneider K, Zonneveld M, Allikmets R, van den Born LI, Maugeri
A, Hoyng CB, and Cremers FP (2004b) Microarray-based mutation analysis of the ABCA4
(ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa. Eur J Hum
Genet 12:1024-1032
190. Kloeckener-Gruissem B and Amstutz Ch (2009) VCAN-Related Vitreoretinopathy.
GeneReviews at GeneTests: Medical Genetics Information Resource [database online]
Copyright,University of Washington,Seattle,1997-2008
191. Kloeckener-Gruissem B, Bartholdi D, Abdou MT, Zimmermann DR, and Berger W (2006)
Identification of the genetic defect in the original Wagner syndrome family. Mol Vis 12:350-355
192. Koenekoop RK, Lopez I, den Hollander AI, Allikmets R, and Cremers FP (2007) Genetic
testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions. Clin
Experiment Ophthalmol 35:473-485
193. Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U, Spegal R, Anastasi M,
Zrenner E, Sharpe LT, and Wissinger B (2000) Mutations in the CNGB3 gene encoding the
beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for
achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet 9:2107-2116
194. Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, and
Wissinger B (2002) Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2
in patients with achromatopsia. Am J Hum Genet 71:422-425
195. Kohl S, Marx T, Giddings I, Jagle H, Jacobson SG, Apfelstedt-Sylla E, Zrenner E, Sharpe LT,
and Wissinger B (1998) Total colourblindness is caused by mutations in the gene encoding
the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 19:257259
196. Kondo H, Qin M, Kusaka S, Tahira T, Hasebe H, Hayashi H, Uchio E, and Hayashi K (2007)
Novel mutations in norrie disease gene in Japanese patients with norrie disease and familial
exudative vitreoretinopathy. Invest Ophthalmol Vis Sci 48:1276-1282
197. Kopan R and Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the
activation mechanism. Cell 137:216-233
198. Kousi M, Siintola E, Dvorakova L, Vlaskova H, Turnbull J, Topcu M, Yuksel D, Gokben S,
Minassian BA, Elleder M, Mole SE, and Lehesjoki AE (2009) Mutations in CLN7/MFSD8 are a
common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain 132:810-819
199. Kumaramanickavel G, Maw M, Denton MJ, John S, Srikumari CR, Orth U, Oehlmann R, and
Gal A (1994) Missense rhodopsin mutation in a family with recessive RP. Nat Genet 8:10-11
74
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
200. Lam BL, Goldberg JL, Hartley KL, Stone EM, and Liu M (2007) Atypical mild enhanced S-cone
syndrome with novel compound heterozygosity of the NR2E3 gene. Am J Ophthalmol
144:157-159
201. Lanza RP, Hayes JL, and Chick WL (1996) Encapsulated cell technology. Nat Biotechnol
14:1107-1111
202. Lau LI, Chen SJ, Cheng CY, Yen MY, Lee FL, Lin MW, Hsu WM, and Wei YH (2006)
Association of the Y402H polymorphism in complement factor H gene and neovascular agerelated macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci 47:3242-3246
203. Lee MM, Ritter R, III, Hirose T, Vu CD, and Edwards AO (2003) Snowflake vitreoretinal
degeneration: follow-up of the original family. Ophthalmology 110:2418-2426
204. Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, Knowles MR, and Zariwala
MA (2009a) Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome.
Genet Med 11:473-487
205. Leigh MW, Zariwala MA, and Knowles MR (2009b) Primary ciliary dyskinesia: improving the
diagnostic approach. Curr Opin Pediatr 21:320-325
206. Li G, Vega R, Nelms K, Gekakis N, Goodnow C, McNamara P, Wu H, Hong NA, and Glynne
R (2007) A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular
quiescence. PLoS Genet 3:e8207. Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L,
Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, GuayWoodford LM, Yoder BK, Stormo GD, Katsanis N, and Dutcher SK (2004) Comparative
genomics identifies a flagellar and basal body proteome that includes the BBS5 human
disease gene. Cell 117:541-552
208. Li Y, Dong B, Hu AL, Cui TT, and Zheng YY (2005) A novel RPGR gene mutation in a
Chinese family with X-linked dominant retinitis pigmentosa. Zhonghua Yi Xue Yi Chuan Xue
Za Zhi 22:396-398
209. Li Z, Sergouniotis PI, Michaelides M, Mackay DS, Wright GA, Devery S, Moore AT, Holder GE,
Robson AG, and Webster AR (2009) Recessive Mutations of the Gene TRPM1 Abrogate ON
Bipolar Cell Function and Cause Complete Congenital Stationary Night Blindness in Humans.
Am J Hum Genet 85:711-719
210. Lin JM, Wan L, Tsai YY, Lin HJ, Tsai Y, Lee CC, Tsai CH, Tseng SH, and Tsai FJ (2008)
Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration.
Am J Ophthalmol 145:1045-1051
211. Liu X, Bulgakov OV, Darrow KN, Pawlyk B, Adamian M, Liberman MC, and Li T (2007)
Usherin is required for maintenance of retinal photoreceptors and normal development of
cochlear hair cells. Proc Natl Acad Sci U S A 104:4413-4418
212. Liu X, Udovichenko IP, Brown SD, Steel KP, and Williams DS (1999) Myosin VIIa participates
in opsin transport through the photoreceptor cilium. J Neurosci 19:6267-6274
213. Loges NT, Olbrich H, Fenske L, Mussaffi H, Horvath J, Fliegauf M, Kuhl H, Baktai G, Peterffy
E, Chodhari R, Chung EM, Rutman A, O'Callaghan C, Blau H, Tiszlavicz L, Voelkel K, Witt M,
Zietkiewicz E, Neesen J, Reinhardt R, Mitchison HM, and Omran H (2008) DNAI2 mutations
cause primary ciliary dyskinesia with defects in the outer dynein arm. Am J Hum Genet
83:547-558
214. Lonka L, Kyttala A, Ranta S, Jalanko A, and Lehesjoki AE (2000) The neuronal ceroid
lipofuscinosis CLN8 membrane protein is a resident of the endoplasmic reticulum. Hum Mol
Genet 9:1691-1697
75
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
215. Lotery A and Trump D (2007) Progress in defining the molecular biology of age related
macular degeneration. Hum Genet 122:219-236
216. Luhmann UF, Lin J, Acar N, Lammel S, Feil S, Grimm C, Seeliger MW, Hammes HP, and
Berger W (2005a) Role of the Norrie disease pseudoglioma gene in sprouting angiogenesis
during development of the retinal vasculature. Invest Ophthalmol Vis Sci 46:3372-3382
217. Luhmann UF, Meunier D, Shi W, Luttges A, Pfarrer C, Fundele R, and Berger W (2005b) Fetal
loss in homozygous mutant Norrie disease mice: a new role of Norrin in reproduction. Genesis
42:253-262
218. Luhmann UF, Neidhardt J, Kloeckener-Gruissem B, Schafer NF, Glaus E, Feil S, and Berger
W (2008) Vascular changes in the cerebellum of Norrin /Ndph knockout mice correlate with
high expression of Norrin and Frizzled-4. Eur J Neurosci 27:2619-2628
219. Mackness MI, Arrol S, Abbott C, and Durrington PN (1993) Protection of low-density
lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase.
Atherosclerosis 104:129-135
220. Maeda A, Crabb JW, and Palczewski K (2005) Microsomal glutathione S-transferase 1 in the
retinal pigment epithelium: protection against oxidative stress and a potential role in aging.
Biochemistry 44:480-489
221. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Jr., Mingozzi F, Bennicelli J, Banfi S, Marshall
KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs
J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS,
Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, and Bennett J (2008)
Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med
358:2240-2248
222. Majava M, Hoornaert KP, Bartholdi D, Bouma MC, Bouman K, Carrera M, Devriendt K, Hurst
J, Kitsos G, Niedrist D, Petersen MB, Shears D, Stolte-Dijkstra I, Van Hagen JM, Ala-Kokko L,
Mannikko M, and Mortier GR (2007) A report on 10 new patients with heterozygous mutations
in the COL11A1 gene and a review of genotype-phenotype correlations in type XI
collagenopathies. Am J Med Genet A 143:258-264
223. Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, and Seddon JM (2006)
Common variation in three genes, including a noncoding variant in CFH, strongly influences
risk of age-related macular degeneration. Nature Genetics 38:1055-1059
224. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, and Seddon JM (2007) Variation
in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet
39:1200-1201
225. Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond
TM, Arnaud B, Claustres M, and Hamel CP (1997) Mutations in RPE65 cause Leber's
congenital amaurosis. Nat Genet 17:139-141
226. Marshall JD, Hinman EG, Collin GB, Beck S, Cerqueira R, Maffei P, Milan G, Zhang W,
Wilson DI, Hearn T, Tavares P, Vettor R, Veronese C, Martin M, So WV, Nishina PM, and
Naggert JK (2007) Spectrum of ALMS1 variants and evaluation of genotype-phenotype
correlations in Alstrom syndrome. Hum Mutat 28:1114-1123
227. Martinez-Mir A, Paloma E, Allikmets R, Ayuso C, del Rio T, Dean M, Vilageliu L, GonzalezDuarte R, and Balcells S (1998) Retinitis pigmentosa caused by a homozygous mutation in
the Stargardt disease gene ABCR. Nat Genet 18:11-12
228. Matsumoto N, Tamura S, Furuki S, Miyata N, Moser A, Shimozawa N, Moser HW, Suzuki Y,
Kondo N, and Fujiki Y (2003) Mutations in novel peroxin gene PEX26 that cause peroxisomebiogenesis disorders of complementation group 8 provide a genotype-phenotype correlation.
Am J Hum Genet 73:233-246
76
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
229. Maugeri A, Klevering BJ, Rohrschneider K, Blankenagel A, Brunner HG, Deutman AF, Hoyng
CB, and Cremers FP (2000) Mutations in the ABCA4 (ABCR) gene are the major cause of
autosomal recessive cone-rod dystrophy. Am J Hum Genet 67:960-966
230. Maugeri A, van Driel MA, van de Pol DJ, Klevering BJ, van Haren FJ, Tijmes N, Bergen AA,
Rohrschneider K, Blankenagel A, Pinckers AJ, Dahl N, Brunner HG, Deutman AF, Hoyng CB,
and Cremers FP (1999) The 2588G-->C mutation in the ABCR gene is a mild frequent founder
mutation in the Western European population and allows the classification of ABCR mutations
in patients with Stargardt disease. Am J Hum Genet 64:1024-1035
231. Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, Kumaramanickavel G,
John S, Nancarrow D, Roper K, Weigmann A, Huttner WB, and Denton MJ (2000) A
frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol
Genet 9:27-34
232. Maw MA, Kennedy B, Knight A, Bridges R, Roth KE, Mani EJ, Mukkadan JK, Nancarrow D,
Crabb JW, and Denton MJ (1997) Mutation of the gene encoding cellular retinaldehydebinding protein in autosomal recessive retinitis pigmentosa. Nat Genet 17:198-200
233. McAlinden A, Liang L, Mukudai Y, Imamura T, and Sandell LJ (2007) Nuclear protein TIA-1
regulates COL2A1 alternative splicing and interacts with precursor mRNA and genomic DNA.
J Biol Chem 282:24444-24454
234. McAlinden A, Majava M, Bishop PN, Perveen R, Black GC, Pierpont ME, Ala-Kokko L, and
Mannikko M (2008) Missense and nonsense mutations in the alternatively-spliced exon 2 of
COL2A1 cause the ocular variant of Stickler syndrome. Hum Mutat 29:83-90
235. McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, and Spinner NB
(2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch
signaling pathway. Am J Hum Genet 79:169-173
236. McKie AB, McHale JC, Keen TJ, Tarttelin EE, Goliath R, Lith-Verhoeven JJ, Greenberg J,
Ramesar RS, Hoyng CB, Cremers FP, Mackey DA, Bhattacharya SS, Bird AC, Markham AF,
and Inglehearn CF (2001) Mutations in the pre-mRNA splicing factor gene PRPC8 in
autosomal dominant retinitis pigmentosa (RP13). Hum Mol Genet 10:1555-1562
237. McLaughlin ME, Sandberg MA, Berson EL, and Dryja TP (1993) Recessive mutations in the
gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa.
Nat Genet 4:130-134
238. McTaggart KE, Tran M, Mah DY, Lai SW, Nesslinger NJ, and MacDonald IM (2002)
Mutational analysis of patients with the diagnosis of choroideremia. Hum Mutat 20:189-196
239. Meindl A, Berger W, Meitinger T, van de PD, Achatz H, Dorner C, Haasemann M, Hellebrand
H, Gal A, Cremers F, and Ropers HH (1992) Norrie disease is caused by mutations in an
extracellular protein resembling C-terminal globular domain of mucins. Nat Genet 2:139-143
240. Meindl A, Dry K, Herrmann K, Manson F, Ciccodicola A, Edgar A, Carvalho MR, Achatz H,
Hellebrand H, Lennon A, Migliaccio C, Porter K, Zrenner E, Bird A, Jay M, Lorenz B, Wittwer B,
D'Urso M, Meitinger T, and Wright A (1996) A gene (RPGR) with homology to the RCC1
guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat
Genet 13:35-42
241. Meindl A, Lorenz B, Achatz H, Hellebrand H, Schmitz-Valckenberg P, and Meitinger T (1995)
Missense mutations in the NDP gene in patients with a less severe course of Norrie disease.
Hum Mol Genet 4:489-490
242. Mendes HF, van der SJ, Chapple JP, and Cheetham ME (2005) Mechanisms of cell death in
rhodopsin retinitis pigmentosa: implications for therapy. Trends Mol Med 11:177-185
77
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
243. Meredith SP, Richards AJ, Flanagan DW, Scott JD, Poulson AV, and Snead MP (2006)
Clinical characterisation and molecular analysis of Wagner syndrome. Br J Ophthalmol
244. Merry DE, Janne PA, Landers JE, Lewis RA, and Nussbaum RL (1992) Isolation of a
candidate gene for choroideremia. Proc Natl Acad Sci U S A 89:2135-2139
245. Michaelides M, Holder GE, Bradshaw K, Hunt DM, Mollon JD, and Moore AT (2004)
Oligocone trichromacy: a rare and unusual cone dysfunction syndrome. Br J Ophthalmol
88:497-500
246. Milam AH, Rose L, Cideciyan AV, Barakat MR, Tang WX, Gupta N, Aleman TS, Wright AF,
Stone EM, Sheffield VC, and Jacobson SG (2002) The nuclear receptor NR2E3 plays a role in
human retinal photoreceptor differentiation and degeneration. Proc Natl Acad Sci U S A
99:473-478
247. Millington-Ward S, O'Neill B, Tuohy G, Al Jandal N, Kiang AS, Kenna PF, Palfi A, Hayden P,
Mansergh F, Kennan A, Humphries P, and Farrar GJ (1997) Strategems in vitro for gene
therapies directed to dominant mutations. Hum Mol Genet 6:1415-1426
248. Mitchell GA, Brody LC, Looney J, Steel G, Suchanek M, Dowling C, Der K, V, Kaiser-Kupfer M,
and Valle D (1988) An initiator codon mutation in ornithine-delta-aminotransferase causing
gyrate atrophy of the choroid and retina. J Clin Invest 81:630-633
249. Miyamoto T, Inoue H, Sakamoto Y, Kudo E, Naito T, Mikawa T, Mikawa Y, Isashiki Y, Osabe
D, Shinohara S, Shiota H, and Itakura M (2005) Identification of a novel splice site mutation of
the CSPG2 gene in a Japanese family with Wagner syndrome. Invest Ophthalmol Vis Sci
46:2726-2735
250. Mole SE, Michaux G, Codlin S, Wheeler RB, Sharp JD, and Cutler DF (2004) CLN6, which is
associated with a lysosomal storage disease, is an endoplasmic reticulum protein. Exp Cell
Res 298:399-406
251. Mollet G, Salomon R, Gribouval O, Silbermann F, Bacq D, Landthaler G, Milford D, Nayir A,
Rizzoni G, Antignac C, and Saunier S (2002) The gene mutated in juvenile nephronophthisis
type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet 32:300-305
252. Moore A, Escudier E, Roger G, Tamalet A, Pelosse B, Marlin S, Clement A, Geremek M,
Delaisi B, Bridoux AM, Coste A, Witt M, Duriez B, and Amselem S (2006) RPGR is mutated in
patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis
pigmentosa. J Med Genet 43:326-333
253. Moosajee M, Tulloch M, Baron RA, Gregory-Evans CY, Pereira-Leal JB, and Seabra MC
(2009) Single choroideremia gene in nonmammalian vertebrates explains early embryonic
lethality of the zebrafish model of choroideremia. Invest Ophthalmol Vis Sci 50:3009-3016
254. Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, and Dryja TP (1998) Mutations
in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber
congenital amaurosis. Proc Natl Acad Sci U S A 95:3088-3093
255. Morimura H, Saindelle-Ribeaudeau F, Berson EL, and Dryja TP (1999) Mutations in RGR,
encoding a light-sensitive opsin homologue, in patients with retinitis pigmentosa. Nat Genet
23:393-394
256. Mukhopadhyay A, Nikopoulos K, Maugeri A, de Brouwer AP, van Nouhuys CE, Boon CJ,
Perveen R, Zegers HA, Wittebol-Post D, van den Biesen PR, van der Velde-Visser SD,
Brunner HG, Black GC, Hoyng CB, and Cremers FP (2006) Erosive vitreoretinopathy and
wagner disease are caused by intronic mutations in CSPG2/Versican that result in an
imbalance of splice variants. Invest Ophthalmol Vis Sci 47:3565-3572
257. Mustafi D, Engel AH, and Palczewski K (2009) Structure of cone photoreceptors. Prog Retin
Eye Res 28:289-302
78
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
258. Mykytyn K, Braun T, Carmi R, Haider NB, Searby CC, Shastri M, Beck G, Wright AF,
Iannaccone A, Elbedour K, Riise R, Baldi A, Raas-Rothschild A, Gorman SW, Duhl DM,
Jacobson SG, Casavant T, Stone EM, and Sheffield VC (2001) Identification of the gene that,
when mutated, causes the human obesity syndrome BBS4. Nat Genet 28:188-191
259. Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, Braun T, Streb LM,
Cornier AS, Cox GF, Fulton AB, Carmi R, Luleci G, Chandrasekharappa SC, Collins FS,
Jacobson SG, Heckenlively JR, Weleber RG, Stone EM, and Sheffield VC (2002)
Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a
complex human obesity syndrome. Nat Genet 31:435-438
260. Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peranen J, Merdes A, Slusarski DC, Scheller
RH, Bazan JF, Sheffield VC, and Jackson PK (2007) A core complex of BBS proteins
cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129:12011213
261. Nakazawa M, Kikawa E, Chida Y, and Tamai M (1994) Asn244His mutation of the
peripherin/RDS gene causing autosomal dominant cone-rod degeneration. Hum Mol Genet
3:1195-1196
262. Nakazawa M, Wada Y, and Tamai M (1998) Arrestin gene mutations in autosomal recessive
retinitis pigmentosa. Arch Ophthalmol 116:498-501
263. Narayanan R, Butani V, Boyer DS, Atilano SR, Resende GP, Kim DS, Chakrabarti S,
Kuppermann BD, Khatibi N, Chwa M, Nesburn AB, and Kenney MC (2007) Complement
factor H polymorphism in age-related macular degeneration. Ophthalmology 114:1327-1331
264. Nathans J, Thomas D, and Hogness DS (1986) Molecular genetics of human color vision: the
genes encoding blue, green, and red pigments. Science 232:193-202
265. Neidhardt J, Barthelmes D, Farahmand F, Fleischhauer JC, and Berger W (2006) Different
amino acid substitutions at the same position in rhodopsin lead to distinct phenotypes. Invest
Ophthalmol Vis Sci 47:1630-1635
266. Neidhardt J, Glaus E, Barthelmes D, Zeitz C, Fleischhauer J, and Berger W (2007)
Identification and characterization of a novel RPGR isoform in human retina. Hum Mutat
28:797-807
267. Neidhardt J, Glaus E, Lorenz B, Netzer C, Li Y, Schambeck M, Wittmer M, Feil S, KirschnerSchwabe R, Rosenberg T, Cremers FP, Bergen AA, Barthelmes D, Baraki H, Schmid F,
Tanner G, Fleischhauer J, Orth U, Becker C, Wegscheider E, Nurnberg G, Nurnberg P, Bolz
HJ, Gal A, and Berger W (2008) Identification of novel mutations in X-linked retinitis
pigmentosa families and implications for diagnostic testing. Mol Vis 14:1081-1093
268. Neidhardt J, Wycisk K, and Klockener-Gruissem B (2005) [Viral and nonviral gene therapy for
treatment of retinal diseases]. Ophthalmologe 102:764-771
269. Nikopoulos K, Gilissen C, Hoischen A, Erik vN, Boonstra FN, Blokland EA, Arts P, Wieskamp
N, Strom TM, Ayuso C, Tilanus MA, Bouwhuis S, Mukhopadhyay A, Scheffer H, Hoefsloot LH,
Veltman JA, Cremers FP, and Collin RW (2010) Next-Generation Sequencing of a 40 Mb
Linkage Interval Reveals TSPAN12 Mutations in Patients with Familial Exudative
Vitreoretinopathy. Am J Hum Genet 86:240-247
270. Nishimura DY, Fath M, Mullins RF, Searby C, Andrews M, Davis R, Andorf JL, Mykytyn K,
Swiderski RE, Yang B, Carmi R, Stone EM, and Sheffield VC (2004) Bbs2-null mice have
neurosensory deficits, a defect in social dominance, and retinopathy associated with
mislocalization of rhodopsin. Proc Natl Acad Sci U S A 101:16588-16593
271. Nishimura DY, Searby CC, Carmi R, Elbedour K, Van Maldergem L, Fulton AB, Lam BL,
Powell BR, Swiderski RE, Bugge KE, Haider NB, Kwitek-Black AE, Ying L, Duhl DM, Gorman
SW, Heon E, Iannaccone A, Bonneau D, Biesecker LG, Jacobson SG, Stone EM, and
79
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
Sheffield VC (2001) Positional cloning of a novel gene on chromosome 16q causing BardetBiedl syndrome (BBS2). Hum Mol Genet 10:865-874
272. Nishimura DY, Swiderski RE, Searby CC, Berg EM, Ferguson AL, Hennekam R, Merin S,
Weleber RG, Biesecker LG, Stone EM, and Sheffield VC (2005) Comparative genomics and
gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum
Genet 77:1021-1033
273. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS,
Spinner NB, Collins FS, and Chandrasekharappa SC (1997) Mutations in the human Jagged1
gene are responsible for Alagille syndrome. Nat Genet 16:235-242
274. Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, Tsuchiya A, Ueta Y,
Soma A, Kanda H, Matsumoto M, and Kawaichi M (2004) HtrA1 serine protease inhibits
signaling mediated by Tgfbeta family proteins. Development 131:1041-1053
275. Olbrich H, Fliegauf M, Hoefele J, Kispert A, Otto E, Volz A, Wolf MT, Sasmaz G, Trauer U,
Reinhardt R, Sudbrak R, Antignac C, Gretz N, Walz G, Schermer B, Benzing T, Hildebrandt F,
and Omran H (2003) Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis,
tapeto-retinal degeneration and hepatic fibrosis. Nat Genet 34:455-459
276. Omran H, Kobayashi D, Olbrich H, Tsukahara T, Loges NT, Hagiwara H, Zhang Q, Leblond G,
O'Toole E, Hara C, Mizuno H, Kawano H, Fliegauf M, Yagi T, Koshida S, Miyawaki A,
Zentgraf H, Seithe H, Reinhardt R, Watanabe Y, Kamiya R, Mitchell DR, and Takeda H (2008)
Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal dyneins. Nature 456:611-616
277. Oshima Y, Ishibashi T, Murata T, Tahara Y, Kiyohara Y, and Kubota T (2001) Prevalence of
age related maculopathy in a representative Japanese population: the Hisayama study. Br J
Ophthalmol 85:1153-1157
278. Otto EA, Schermer B, Obara T, O'Toole JF, Hiller KS, Mueller AM, Ruf RG, Hoefele J,
Beekmann F, Landau D, Foreman JW, Goodship JA, Strachan T, Kispert A, Wolf MT,
Gagnadoux MF, Nivet H, Antignac C, Walz G, Drummond IA, Benzing T, and Hildebrandt F
(2003) Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic
disease to the function of primary cilia and left-right axis determination. Nat Genet 34:413-420
279. Park KH, Ryu E, Tosakulwong N, Wu Y, and Edwards AO (2009) Common variation in the
SERPING1 gene is not associated with age-related macular degeneration in two independent
groups of subjects. Mol Vis 15:200-207
280. Patel N, Adewoyin T, and Chong NV (2008) Age-related macular degeneration: a perspective
on genetic studies. Eye 22:768-776
281. Pennarun G, Escudier E, Chapelin C, Bridoux AM, Cacheux V, Roger G, Clement A,
Goossens M, Amselem S, and Duriez B (1999) Loss-of-function mutations in a human gene
related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J
Hum Genet 65:1508-1519
282. Perrault I, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, Defoort-Dhellemmes S, Dollfus
H, Fazzi E, Munnich A, Kaplan J, and Rozet JM (2007) Spectrum of NPHP6/CEP290
mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum
Mutat 28:416-426
283. Perveen R, Hart-Holden N, Dixon MJ, Wiszniewski W, Fryer AE, Brunner HG, Pinkners AJ,
van Beersum SE, and Black GC (1999) Refined genetic and physical localization of the
Wagner disease (WGN1) locus and the genes CRTL1 and CSPG2 to a 2- to 2.5-cM region of
chromosome 5q14.3. Genomics 57:219-226
284. Piccoli DA and Spinner NB (2001) Alagille syndrome and the Jagged1 gene. Semin Liver Dis
21:525-534
80
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
285. Pieramici DJ and Rabena MD (2008) Anti-VEGF therapy: comparison of current and future
agents. Eye 22:1330-1336
286. Pierce EA, Quinn T, Meehan T, McGee TL, Berson EL, and Dryja TP (1999) Mutations in a
gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis
pigmentosa. Nat Genet 22:248-254
287. Poloschek CM, Kloeckener-Gruissem B, Hansen LL, Bach M, and Berger W (2008)
Syndromic choroideremia: sublocalization of phenotypes associated with Martin-Probst
deafness mental retardation syndrome. Invest Ophthalmol Vis Sci 49:4096-4104
288. Poulter JA, Ali M, Gilmour DF, Rice A, Kondo H, Hayashi K, Mackey DA, Kearns LS, Ruddle
JB, Craig JE, Pierce EA, Downey LM, Mohamed MD, Markham AF, Inglehearn CF, and
Toomes C (2010) Mutations in TSPAN12 Cause Autosomal-Dominant Familial Exudative
Vitreoretinopathy. Am J Hum Genet 86:248-253
289. Preising M and Ayuso C (2004) Rab escort protein 1 (REP1) in intracellular traffic: a functional
and pathophysiological overview. Ophthalmic Genet 25:101-110
290. Pusch CM, Zeitz C, Brandau O, Pesch K, Achatz H, Feil S, Scharfe C, Maurer J, Jacobi FK,
Pinckers A, Andreasson S, Hardcastle A, Wissinger B, Berger W, and Meindl A (2000) The
complete form of X-linked congenital stationary night blindness is caused by mutations in a
gene encoding a leucine-rich repeat protein. Nat Genet 26:324-327
291. Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, Sharp J, Wheeler R, Kusumi K,
Mole S, Liu W, Soares MB, Bonaldo MF, Hirvasniemi A, de la CA, Gilliam TC, and Lehesjoki
AE (1999) The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are
associated with mutations in CLN8. Nat Genet 23:233-236
292. Rao VR, Cohen GB, and Oprian DD (1994) Rhodopsin mutation G90D and a molecular
mechanism for congenital night blindness. Nature 367:639-642
293. Rebello G, Ramesar R, Vorster A, Roberts L, Ehrenreich L, Oppon E, Gama D, Bardien S,
Greenberg J, Bonapace G, Waheed A, Shah GN, and Sly WS (2004) Apoptosis-inducing
signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of
retinitis pigmentosa. Proc Natl Acad Sci U S A 101:6617-6622
294. Richards AJ, Meredith S, Poulson A, Bearcroft P, Crossland G, Baguley DM, Scott JD, and
Snead MP (2005) A novel mutation of COL2A1 resulting in dominantly inherited
rhegmatogenous retinal detachment. Invest Ophthalmol Vis Sci 46:663-668
295. Richards AJ, Scott JD, and Snead MP (2002) Molecular genetics of rhegmatogenous retinal
detachment. Eye 16:388-392
296. Richardson AJ, Islam FM, Guymer RH, Cain M, and Baird PN (2007) A tag-single nucleotide
polymorphisms approach to the vascular endothelial growth factor-A gene in age-related
macular degeneration. Mol Vis 13:2148-2152
297. Rio FT, Wade NM, Ransijn A, Berson EL, Beckmann JS, and Rivolta C (2008) Premature
termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to
nonsense-mediated mRNA decay. J Clin Invest 118:1519-1531
298. Riveiro-Alvarez R, Trujillo-Tiebas MJ, Gimenez-Pardo A, Garcia-Hoyos M, Cantalapiedra D,
Lorda-Sanchez I, Rodriguez dA, Ramos C, and Ayuso C (2005) Genotype-phenotype
variations in five Spanish families with Norrie disease or X-linked FEVR. Mol Vis 11:705-712
299. Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, and Weber BHF
(2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular
degeneration, contributing independently of complement factor H to disease risk. Hum Mol
Genet 14:3227-3236
81
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
300. Rivolta C, Sweklo EA, Berson EL, and Dryja TP (2000) Missense mutation in the USH2A gene:
association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet
66:1975-1978
301. Robitaille J, MacDonald ML, Kaykas A, Sheldahl LC, Zeisler J, Dube MP, Zhang LH, Singaraja
RR, Guernsey DL, Zheng B, Siebert LF, Hoskin-Mott A, Trese MT, Pimstone SN, Shastry BS,
Moon RT, Hayden MR, Goldberg YP, and Samuels ME (2002) Mutant frizzled-4 disrupts
retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 32:326-330
302. Roepman R, Bauer D, Rosenberg T, van Duijnhoven G, van d, V, Platzer M, Rosenthal A,
Ropers HH, Cremers FP, and Berger W (1996a) Identification of a gene disrupted by a
microdeletion in a patient with X-linked retinitis pigmentosa (XLRP). Hum Mol Genet 5:827833
303. Roepman R, Bernoud-Hubac N, Schick DE, Maugeri A, Berger W, Ropers HH, Cremers FP,
and Ferreira PA (2000) The retinitis pigmentosa GTPase regulator (RPGR) interacts with
novel transport-like proteins in the outer segments of rod photoreceptors. Hum Mol Genet
9:2095-2105
304. Roepman R, van Duijnhoven G, Rosenberg T, Pinckers AJ, Bleeker-Wagemakers LM, Bergen
AA, Post J, Beck A, Reinhardt R, Ropers HH, Cremers FP, and Berger W (1996b) Positional
cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotideexchange factor RCC1. Hum Mol Genet 5:1035-1041
305. Ronan SM, Tran-Viet KN, Burner EL, Metlapally R, Toth CA, and Young TL (2009) Mutational
hot spot potential of a novel base pair mutation of the CSPG2 gene in a family with Wagner
syndrome. Arch Ophthalmol 127:1511-1519
306. Rosenberg T, Baumann B, Kohl S, Zrenner E, Jorgensen AL, and Wissinger B (2004) Variant
phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations. Invest
Ophthalmol Vis Sci 45:4256-4262
307. Royer G, Hanein S, Raclin V, Gigarel N, Rozet JM, Munnich A, Steffann J, Dufier JL, Kaplan J,
and Bonnefont JP (2003) NDP gene mutations in 14 French families with Norrie disease. Hum
Mutat 22:499308. Rozet JM, Gerber S, Souied E, Perrault I, Chatelin S, Ghazi I, Leowski C, Dufier JL, Munnich
A, and Kaplan J (1998) Spectrum of ABCR gene mutations in autosomal recessive macular
dystrophies. Eur J Hum Genet 6:291-295
309. Rozet JM, Perrault I, Gigarel N, Souied E, Ghazi I, Gerber S, Dufier JL, Munnich A, and
Kaplan J (2002) Dominant X linked retinitis pigmentosa is frequently accounted for by
truncating mutations in exon ORF15 of the RPGR gene. J Med Genet 39:284-285
310. Ruddle JB, Ebenezer ND, Kearns LS, Mulhall LE, Mackey DA, and Hardcastle AJ (2009)
RPGR ORF15 genotype and clinical variability of retinal degeneration in an Australian
population. Br J Ophthalmol 93:1151-1154
311. Saihan Z, Webster AR, Luxon L, and Bitner-Glindzicz M (2009) Update on Usher syndrome.
Curr Opin Neurol 22:19-27
312. Sandberg MA, Rosner B, Weigel-DiFranco C, Dryja TP, and Berson EL (2007) Disease
course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations. Invest
Ophthalmol Vis Sci 48:1298-1304
313. Sato M, Nakazawa M, Usui T, Tanimoto N, Abe H, and Ohguro H (2005) Mutations in the
gene coding for guanylate cyclase-activating protein 2 (GUCA1B gene) in patients with
autosomal dominant retinal dystrophies. Graefes Arch Clin Exp Ophthalmol 243:235-242
314. Schäfer NF, Luhmann UF, Feil S, and Berger W (2008) Differential gene expression in Ndph
knockout mice in retinal development. Invest Ophthalmol Vis Sci 50:906-916
82
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
315. Schmid F, Glaus E, Cremers FP, Kloeckener-Gruissem B, Berger W, and Neidhardt J (2010)
Mutation- and Tissue-Specific Alterations of RPGR Transcripts. Invest Ophthalmol Vis Sci
51:1628-1635
316. Scholl HP, Charbel IP, Walier M, Janzer S, Pollok-Kopp B, Borncke F, Fritsche LG, Chong NV,
Fimmers R, Wienker T, Holz FG, Weber BH, and Oppermann M (2008) Systemic complement
activation in age-related macular degeneration. PLoS ONE 3:e2593317. Scholl HP, Fleckenstein M, Charbel IP, Keilhauer C, Holz FG, and Weber BH (2007) An
update on the genetics of age-related macular degeneration. Mol Vis 13:196-205
318. Schwabe GC, Hoffmann K, Loges NT, Birker D, Rossier C, de Santi MM, Olbrich H, Fliegauf
M, Failly M, Liebers U, Collura M, Gaedicke G, Mundlos S, Wahn U, Blouin JL, Niggemann B,
Omran H, Antonarakis SE, and Bartoloni L (2008) Primary ciliary dyskinesia associated with
normal axoneme ultrastructure is caused by DNAH11 mutations. Hum Mutat 29:289-298
319. Schwahn U, Lenzner S, Dong J, Feil S, Hinzmann B, van Duijnhoven G, Kirschner R,
Hemberger M, Bergen AA, Rosenberg T, Pinckers AJ, Fundele R, Rosenthal A, Cremers FP,
Ropers HH, and Berger W (1998) Positional cloning of the gene for X-linked retinitis
pigmentosa 2. Nat Genet 19:327-332
320. Seabra MC, Brown MS, and Goldstein JL (1993) Retinal degeneration in choroideremia:
deficiency of rab geranylgeranyl transferase. Science 259:377-381
321. Seabra MC, Mules EH, and Hume AN (2002) Rab GTPases, intracellular traffic and disease.
Trends Mol Med 8:23-30
322. Seddon JM, Reynolds R, and Rosner B (2009) Peripheral retinal drusen and reticular pigment:
association with CFHY402H and CFHrs1410996 genotypes in family and twin studies. Invest
Ophthalmol Vis Sci 50:586-591
323. Shastry BS, Hejtmancik JF, Plager DA, Hartzer MK, and Trese MT (1995) Linkage and
candidate gene analysis of X-linked familial exudative vitreoretinopathy. Genomics 27:341-344
324. Shastry BS, Hejtmancik JF, and Trese MT (1997a) Identification of novel missense mutations
in the Norrie disease gene associated with one X-linked and four sporadic cases of familial
exudative vitreoretinopathy. Hum Mutat 9:396-401
325. Shastry BS, Hiraoka M, Trese DC, and Trese MT (1999) Norrie disease and exudative
vitreoretinopathy in families with affected female carriers. Eur J Ophthalmol 9:238-242
326. Shastry BS, Pendergast SD, Hartzer MK, Liu X, and Trese MT (1997b) Identification of
missense mutations in the Norrie disease gene associated with advanced retinopathy of
prematurity. Arch Ophthalmol 115:651-655
327. Shima C, Kusaka S, Kondo H, Hasebe H, Fujikado T, and Tano Y (2009) Lens-sparing
vitrectomy effective for reattachment of newly developed falciform retinal detachment in a
patient with Norrie disease. Arch Ophthalmol 127:579-580
328. Shimozawa N, Imamura A, Zhang Z, Suzuki Y, Orii T, Tsukamoto T, Osumi T, Fujiki Y,
Wanders RJ, Besley G, and Kondo N (1999) Defective PEX gene products correlate with the
protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome
biogenesis disorders. J Med Genet 36:779-781
329. Shu X, Black GC, Rice JM, Hart-Holden N, Jones A, O'Grady A, Ramsden S, and Wright AF
(2007) RPGR mutation analysis and disease: an update. Hum Mutat 28:322-328
330. Sieving PA, Fowler ML, Bush RA, Machida S, Calvert PD, Green DG, Makino CL, and
McHenry CL (2001) Constitutive "light" adaptation in rods from G90D rhodopsin: a mechanism
for human congenital nightblindness without rod cell loss. J Neurosci 21:5449-5460
83
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
331. Sieving PA, Richards JE, Naarendorp F, Bingham EL, Scott K, and Alpern M (1995) Dark-light:
model for nightblindness from the human rhodopsin Gly-90-->Asp mutation. Proc Natl Acad
Sci U S A 92:880-884
332. Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, Lehesjoki AE, and
Tyynela J (2006) Cathepsin D deficiency underlies congenital human neuronal ceroidlipofuscinosis. Brain 129:1438-1445
333. Siintola E, Topcu M, Aula N, Lohi H, Minassian BA, Paterson AD, Liu XQ, Wilson C, Lahtinen
U, Anttonen AK, and Lehesjoki AE (2007) The novel neuronal ceroid lipofuscinosis gene
MFSD8 encodes a putative lysosomal transporter. Am J Hum Genet 81:136-146
334. Sims KB, Irvine AR, and Good WV (1997) Norrie disease in a family with a manifesting female
carrier. Arch Ophthalmol 115:517-519
335. Sirko-Osadsa DA, Murray MA, Scott JA, Lavery MA, Warman ML, and Robin NH (1998)
Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene
encoding the alpha2(XI) chain of type XI collagen. J Pediatr 132:368-371
336. Sivaprasad S and Chong NV (2006) The complement system and age-related macular
degeneration. Eye 20:867-872
337. Sleat DE, Donnelly RJ, Lackland H, Liu CG, Sohar I, Pullarkat RK, and Lobel P (1997)
Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid
lipofuscinosis. Science 277:1802-1805
338. Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, Agarwal A, Postel EA,
Pericak-Vance MA, and Haines JL (2007) Protective effect of complement factor B and
complement component 2 variants in age-related macular degeneration. Hum Mol Genet
16:1986-1992
339. Spencer KL, Olson LM, Anderson BM, Schnetz-Boutaud N, Scott WK, Gallins P, Agarwal A,
Postel EA, Pericak-Vance MA, and Haines JL (2008) C3 R102G polymorphism increases risk
of age-related macular degeneration. Hum Mol Genet 17:1821-1824
340. Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, and Meunier-Rotival M (2001)
Jagged1 mutations in alagille syndrome. Hum Mutat 17:18-33
341. Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Bruck W, Saftig P, and
Gartner J (2006) Cathepsin D deficiency is associated with a human neurodegenerative
disorder. Am J Hum Genet 78:988-998
342. Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, Leitch CC, Salem N, Chouery E,
Corbani S, Jalk N, Vicaire S, Sarda P, Hamel C, Lacombe D, Holder M, Odent S, Holder S,
Brooks AS, Elcioglu NH, Silva ED, Rossillion B, Sigaudy S, de Ravel TJ, Lewis RA, Leheup B,
Verloes A, Amati-Bonneau P, Megarbane A, Poch O, Bonneau D, Beales PL, Mandel JL,
Katsanis N, and Dollfus H (2006) BBS10 encodes a vertebrate-specific chaperonin-like protein
and is a major BBS locus. Nat Genet 38:521-524
343. Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, Jacquelin C, Plewniak F,
Leitch CC, Sarda P, Hamel C, de Ravel TJ, Lewis RA, Friederich E, Thibault C, Danse JM,
Verloes A, Bonneau D, Katsanis N, Poch O, Mandel JL, and Dollfus H (2007) Identification of
a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of
chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet 80:1-11
344. Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K,
Gutwillinger N, Ruther K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, and
Meindl A (1998) An L-type calcium-channel gene mutated in incomplete X-linked congenital
stationary night blindness. Nat Genet 19:260-263
84
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
345. Sullivan LS, Heckenlively JR, Bowne SJ, Zuo J, Hide WA, Gal A, Denton M, Inglehearn CF,
Blanton SH, and Daiger SP (1999) Mutations in a novel retina-specific gene cause autosomal
dominant retinitis pigmentosa. Nat Genet 22:255-259
346. Sun H and Nathans J (1997) Stargardt's ABCR is localized to the disc membrane of retinal rod
outer segments. Nat Genet 17:15-16
347. Sun H, Smallwood PM, and Nathans J (2000) Biochemical defects in ABCR protein variants
associated with human retinopathies. Nat Genet 26:242-246
348. Swaroop A, Branham KE, Chen W, and Abecasis G (2007) Genetic susceptibility to agerelated macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol
Genet 16 Spec No. 2:R174-R182
349. Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, Zhang K, and Attia J (2006)
Systematic review and meta-analysis of the association between complement factor H Y402H
polymorphisms and age-related macular degeneration. Hum Mol Genet 15:2784-2790
350. Thanos CG, Bell WJ, O'Rourke P, Kauper K, Sherman S, Stabila P, and Tao W (2004)
Sustained secretion of ciliary neurotrophic factor to the vitreous, using the encapsulated cell
therapy-based NT-501 intraocular device. Tissue Eng 10:1617-1622
351. Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De
Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, Lith-Verhoeven JJ, Lotery AJ,
Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, and Klaver CC (2009)
Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone
photoreceptor disorders. Am J Hum Genet 85:240-247
352. Thompson DA, Li Y, McHenry CL, Carlson TJ, Ding X, Sieving PA, Apfelstedt-Sylla E, and Gal
A (2001) Mutations in the gene encoding lecithin retinol acyltransferase are associated with
early-onset severe retinal dystrophy. Nat Genet 28:123-124
353. Tolmachova T, Anders R, Abrink M, Bugeon L, Dallman MJ, Futter CE, Ramalho JS, Tonagel
F, Tanimoto N, Seeliger MW, Huxley C, and Seabra MC (2006) Independent degeneration of
photoreceptors and retinal pigment epithelium in conditional knockout mouse models of
choroideremia. J Clin Invest 116:386-394
354. Tschernutter M, Schlichtenbrede FC, Howe S, Balaggan KS, Munro PM, Bainbridge JW,
Thrasher AJ, Smith AJ, and Ali RR (2005) Long-term preservation of retinal function in the
RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy. Gene Ther
12:694-701
355. Tuo J, Bojanowski CM, and Chan CC (2004) Genetic factors of age-related macular
degeneration. Prog Retin Eye Res 23:229-249
356. Tuson M, Marfany G, and Gonzalez-Duarte R (2004) Mutation of CERKL, a novel human
ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). Am J Hum
Genet 74:128-138
357. Valente EM, Brancati F, Silhavy JL, Castori M, Marsh SE, Barrano G, Bertini E, Boltshauser E,
Zaki MS, Abdel-Aleem A, Abdel-Salam GM, Bellacchio E, Battini R, Cruse RP, Dobyns WB,
Krishnamoorthy KS, Lagier-Tourenne C, Magee A, Pascual-Castroviejo I, Salpietro CD, Sarco
D, Dallapiccola B, and Gleeson JG (2006) AHI1 gene mutations cause specific forms of
Joubert syndrome-related disorders. Ann Neurol 59:527-534
358. Valle D, Kaiser-Kupfer MI, and Del Valle LA (1977) Gyrate atrophy of the choroid and retina:
deficiency of ornithine aminotransferase in transformed lymphocytes. Proc Natl Acad Sci U S
A 74:5159-5161
359. Van Camp G, Snoeckx RL, Hilgert N, van den EJ, Fukuoka H, Wagatsuma M, Suzuki H,
Smets RM, Vanhoenacker F, Declau F, Van de HP, and Usami S (2006) A new autosomal
85
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am J Hum
Genet 79:449-457
360. van Genderen MM, Bijveld MM, Claassen YB, Florijn RJ, Pearring JN, Meire FM, McCall MA,
Riemslag FC, Gregg RG, Bergen AA, and Kamermans M (2009) Mutations in TRPM1 Are a
Common Cause of Complete Congenital Stationary Night Blindness. Am J Hum Genet
85:730-736
361. Vernon M (1969) Usher's syndrome--deafness and progressive blindness. Clinical cases,
prevention, theory and literature survey. J Chronic Dis 22:133-151
362. Vervoort R, Lennon A, Bird AC, Tulloch B, Axton R, Miano MG, Meindl A, Meitinger T,
Ciccodicola A, and Wright AF (2000) Mutational hot spot within a new RPGR exon in X-linked
retinitis pigmentosa. Nat Genet 25:462-466
363. Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, Hofmann SL, and
Peltonen L (1995) Mutations in the palmitoyl protein thioesterase gene causing infantile
neuronal ceroid lipofuscinosis. Nature 376:584-587
364. Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, Al Maghtheh M,
Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, and Bhattacharya SS (2001) A human
homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis
pigmentosa on chromosome 19q13.4 (RP11). Mol Cell 8:375-381
365. Voelkerding KV, Dames SA, and Durtschi JD (2009) Next-generation sequencing: from basic
research to diagnostics. Clin Chem 55:641-658
366. Wada Y, Abe T, Takeshita T, Sato H, Yanashima K, and Tamai M (2001) Mutation of human
retinal fascin gene (FSCN2) causes autosomal dominant retinitis pigmentosa. Invest
Ophthalmol Vis Sci 42:2395-2400
367. Wagner H (1938) Ein bisher unbekanntes Erbleiden des Auges, beobachtet im Kanton Zurich.
Klinische Monatsblätter Augenheilkunde 100:840-857
368. Walia S, Fishman GA, Swaroop A, Branham KE, Lindeman M, Othman M, and Weleber RG
(2008) Discordant phenotypes in fraternal twins having an identical mutation in exon ORF15 of
the RPGR gene. Arch Ophthalmol 126:379-384
369. Wang Y, Huso D, Cahill H, Ryugo D, and Nathans J (2001) Progressive cerebellar, auditory,
and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene. J Neurosci
21:4761-4771
370. Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D, Cherel Y, Chenuaud P,
Samulski J, Moullier P, and Rolling F (2003) Recombinant adeno-associated virus serotype 4
mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat,
dog, and nonhuman primate after subretinal delivery. Mol Ther 7:774-781
371. Weger M, Renner W, Steinbrugger I, Kofer K, Wedrich A, Groselj-Strele A, El Shabrawi Y,
Schmut O, and Haas A (2007) Association of the HTRA1 -625G>A promoter gene
polymorphism with exudative age-related macular degeneration in a Central European
population. Mol Vis 13:1274-1279
372. Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J, Mburu P, Varela A, Levilliers J,
Weston MD, and . (1995) Defective myosin VIIA gene responsible for Usher syndrome type
1B. Nature 374:60-61
373. Weleber RG, Carr RE, Murphey WH, Sheffield VC, and Stone EM (1993) Phenotypic variation
including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family
with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol 111:15311542
86
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
374. Williams DS (2008) Usher syndrome: animal models, retinal function of Usher proteins, and
prospects for gene therapy. Vision Res 48:433-441
375. Wissinger B, Gamer D, Jagle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M,
Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C,
Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C,
Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, and Kohl S
(2001) CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet
69:722-737
376. Wu WC, Drenser K, Trese M, Capone A, Jr., and Dailey W (2007) Retinal phenotypegenotype correlation of pediatric patients expressing mutations in the Norrie disease gene.
Arch Ophthalmol 125:225-230
377. Wycisk KA, Zeitz C, Feil S, Wittmer M, Forster U, Neidhardt J, Wissinger B, Zrenner E, Wilke
R, Kohl S, and Berger W (2006) Mutation in the auxiliary calcium-channel subunit CACNA2D4
causes autosomal recessive cone dystrophy. Am J Hum Genet 79:973-977
378. Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L,
Tasman W, Zhang K, and Nathans J (2004) Vascular development in the retina and inner ear:
control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 116:883-895
379. Yamada K, Limprasert P, Ratanasukon M, Tengtrisorn S, Yingchareonpukdee J,
Vasiknanonte P, Kitaoka T, Ghadami M, Niikawa N, and Kishino T (2001) Two Thai families
with Norrie disease (ND): association of two novel missense mutations with severe ND
phenotype, seizures, and a manifesting carrier. Am J Med Genet 100:52-55
380. Yamamoto S, Sippel KC, Berson EL, and Dryja TP (1997) Defects in the rhodopsin kinase
gene in the Oguchi form of stationary night blindness. Nat Genet 15:175-178
381. Yang D, Swaminathan A, Zhang X, and Hughes BA (2008a) Expression of Kir7.1 and a novel
Kir7.1 splice variant in native human retinal pigment epithelium. Experimental Eye Research
86:81-91
382. Yang Z, Peachey NS, Moshfeghi DM, Thirumalaichary S, Chorich L, Shugart YY, Fan K, and
Zhang K (2002) Mutations in the RPGR gene cause X-linked cone dystrophy. Hum Mol Genet
11:605-611
383. Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D, Tong Z, Chen H, Constantine
R, Yang X, Chen Y, Zeng J, Davey L, Ma X, Hau VS, Wang C, Harmon J, Buehler J, Pearson
E, Patel S, Kaminoh Y, Watkins S, Luo L, Zabriskie NA, Bernstein PS, Cho W, Schwager A,
Hinton DR, Klein ML, Hamon SC, Simmons E, Yu B, Campochiaro B, Sunness JS,
Campochiaro P, Jorde L, Parmigiani G, Zack DJ, Katsanis N, Ambati J, and Zhang K (2008b)
Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J
Med 359:1456-1463
384. Yang ZL, Camp NJ, Sun H, Tong ZZ, Gibbs D, Cameron DJ, Chen HY, Zhao Y, Pearson E, Li
X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K,
and Zhang K (2006) A variant of the HTRA1 gene increases susceptibility to age-related
macular degeneration. Science 314:992-993
385. Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B, Messiaen LM, Perveen R, Reddy
MA, Bhattacharya SS, Traboulsi E, Baralle D, De Laey JJ, Puech B, Kestelyn P, Moore AT,
Manson FD, and Black GC (2004) Mutations of VMD2 splicing regulators cause
nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest
Ophthalmol Vis Sci 45:3683-3689
386. Ye X, Wang Y, Cahill H, Yu M, Badea TC, Smallwood PM, Peachey NS, and Nathans J (2009)
Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal
vascularization. Cell 139:285-298
87
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
387. Yuan L, Kawada M, Havlioglu N, Tang H, and Wu JY (2005) Mutations in PRPF31 inhibit premRNA splicing of rhodopsin gene and cause apoptosis of retinal cells. J Neurosci 25:748-757
388. Zangerl B, Goldstein O, Philp AR, Lindauer SJ, Pearce-Kelling SE, Mullins RF, Graphodatsky
AS, Ripoll D, Felix JS, Stone EM, Acland GM, and Aguirre GD (2006) Identical mutation in a
novel retinal gene causes progressive rod-cone degeneration in dogs and retinitis pigmentosa
in humans. Genomics 88:551-563
389. Zareparsi S, Branham KE, Li M, Shah S, Klein RJ, Ott J, Hoh J, Abecasis GR, and Swaroop A
(2005) Strong association of the Y402H variant in complement factor H at 1q32 with
susceptibility to age-related macular degeneration. Am J Hum Genet 77:149-153
390. Zeitz C (2007) Molecular genetics and protein function involved in nocturnal vision. Expert Rev
Ophthalmol 2:467-485
391. Zeitz C, Gross AK, Leifert D, Kloeckener-Gruissem B, McAlear SD, Lemke J, Neidhardt J, and
Berger W (2008) Identification and functional characterization of a novel rhodopsin mutation
associated with autosomal dominant CSNB. Invest Ophthalmol Vis Sci 49:4105-4114
392. Zeitz C, Kloeckener-Gruissem B, Forster U, Kohl S, Magyar I, Wissinger B, Matyas G, Borruat
FX, Schorderet DF, Zrenner E, Munier FL, and Berger W (2006) Mutations in CABP4, the
gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness. Am J
Hum Genet 79:657-667
393. Zeitz C, Labs S, Lorenz B, Forster U, Ueksti J, Kroes HY, De Baere E, Leroy BP, Cremers FP,
Wittmer M, van Genderen MM, Sahel JA, Audo I, Poloschek CM, Mohand-Said S,
Fleischhauer JC, Hueffmeier U, Moskova-Doumanova V, Levin AV, Hamel CP, Leifert D,
Munier FL, Schorderet D, Zrenner E, Friedburg C, Wissinger B, Kohl S, and Berger W (2009)
Genotyping microarray for CSNB-associated genes. Invest Ophthalmol Vis Sci Epub:ahead of
print
394. Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F, Forster U, Wycisk K, Matyas
G, Hoyng CB, Riemslag F, Meire F, Cremers FP, and Berger W (2005) Mutations in GRM6
cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15Hz flicker electroretinogram. Invest Ophthalmol Vis Sci 46:4328-4335
395. Zernant J, Kulm M, Dharmaraj S, den Hollander AI, Perrault I, Preising MN, Lorenz B, Kaplan
J, Cremers FP, Maumenee I, Koenekoop RK, and Allikmets R (2005) Genotyping microarray
(disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest Ophthalmol
Vis Sci 46:3052-3059
396. Zhang Q, Li S, Xiao X, Jia X, and Guo X (2007a) The 208delG mutation in FSCN2 does not
associate with retinal degeneration in Chinese individuals. Invest Ophthalmol Vis Sci 48:530533
397. Zhang Q, Zulfiqar F, Xiao X, Riazuddin SA, Ahmad Z, Caruso R, MacDonald I, Sieving P,
Riazuddin S, and Hejtmancik JF (2007b) Severe retinitis pigmentosa mapped to 4p15 and
associated with a novel mutation in the PROM1 gene. Hum Genet 122:293-299
398. Zhao C, Bellur DL, Lu S, Zhao F, Grassi MA, Bowne SJ, Sullivan LS, Daiger SP, Chen LJ,
Pang CP, Zhao K, Staley JP, and Larsson C (2009) Autosomal-dominant retinitis pigmentosa
caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs. Am J
Hum Genet 85:617-627
399. Zito I, Downes SM, Patel RJ, Cheetham ME, Ebenezer ND, Jenkins SA, Bhattacharya SS,
Webster AR, Holder GE, Bird AC, Bamiou DE, and Hardcastle AJ (2003) RPGR mutation
associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections. J Med
Genet 40:609-615
88
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The molecular basis of human retinal and vitreoretinal diseases
Internet Resources:
ENSEMBL: http://www.ensembl.org/index.html
GeneReviews: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests
GeneTests: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests
MedMolGen: http://www.medmolgen.uzh.ch/index.html
NCBI: http://www.ncbi.nlm.nih.gov/
OMIM: http://www.ncbi.nlm.nih.gov/omim/
Pubmed: http://www.ncbi.nlm.nih.gov/pubmed/
Retnet: http://www.sph.uth.tmc.edu/retnet/
UCSC: http://genome.ucsc.edu/
Acknowledgements:
We would like to acknowledge the work of a large community of medical and basic
researchers, clinicians, counsellors and other professionals, who contributed so
much and significantly to the field. Special thanks go to the patients as well as their
families and we hope that they, or their children, may become the beneficiaries. We
also acknowledge our coworkers in the Division of Medical Molecular Genetics and
Gene Diagnostics (University of Zurich Medical School) and our external
collaborators for their stimulating, enthusiastic and motivated input to our research.
We appreciate support from the funding agencies and patient organizations. Finally,
we would be gratefull to all the readers who are willing to share with us their thoughts
about the different aspects of this review article.
If we have missed to cite any relevant contributions from our colleagues in the field,
we sincerely apologize.
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The molecular basis of human retinal and vitreoretinal diseases
Figure Legends:
Figure 1
Classification of monogenic familial retinal and vitreoretinal diseases. The disorders
are categorized according to the photoreceptor cell type or ocular structure which are
affected by the disease. Rod as well as cone dominated diseases are subdivided in
stationary (yellow) and progressive (red) forms. Generalized photoreceptor diseases
and vitreoretinal diseases are predominantly progressive. The progressive forms are
non-syndromic or part of a multiorgan disease (syndromic). The + signs indicate that
detailed informations and further subclassifications are available in Figures 2 to 5.
Figure 2
Rod over cone photoreceptor diseases. The diseases are either stationary or
progressive. Disease-causing mutations in different genes are dominant, recessive,
or X-linked. In syndromic forms, RP occurs together with disease symptoms in nonocular tissues or organs. The respective genes are indicated by gene symbols.
Figure 3
Cone over rod photoreceptor diseases. The stationary forms affect color vision. The
progressive cone diseases can be subdivided in cone and cone rod dystrophies as
well as macular degenerations. Both occur syndromic or non-syndromic. The
different genes involved in these diseases are indicated by gene symbols. Mutations
are dominant, recessive, or X-linked.
Figure 4
Generalized photoreceptor diseases affect both photoreceptor cell types, rods and
cones. They are progressive in the majority of cases and can occur as part of a
90
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
The molecular basis of human retinal and vitreoretinal diseases
syndrome (syndromic) or not (non-syndromic). Mutations in various genes, indicated
by their symbols, are dominant or recessive. X-linked inheritance has not been
described so far.
Figure 5
Exudative and erosive vitreoretinopathies (ERVR and EVR). Both, syndromic and
non-syndromic forms can be caused by dominant, recessive, or X-linked mutations in
different genes (indicated by gene symbols).
Figure 6
Clinical symptoms of non-syndromic monogenic retinal and vitreoretinal diseases and
their causative genes. Clinical diagnoses are indicated by colored circles. Gene
symbols in the overlapping areas show that mutations in the same gene can lead to
different phenotypes.
RP: retinitis pigmentosa; NB: night blindness; LCA: Leber congenital amaurosis;
CORD/COD: cone-rod and cone dystrophies; CVD: color vision defects; MD: macular
degeneration; ERVR/EVR: erosive and exudative vitreoretinopathies
91
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
Figure 1
Monogenic familial retinal and vitreoretinal diseases
Rod > cone photoreceptor diseases
stationary
progressive
non syndromic
syndromic
Cone > rod photoreceptor diseases
stationary
progressive
Cone & cone rod dystrophies (CODs & CORDs)
non syndromic
syndromic
Macular degenerations (MDs)
non syndromic
Generalized photoreceptor diseases
Vitreoretinopathies (exudative and erosive)
progressive
progressive
non syndromic
syndromic
syndromic
Figure_1 (2).mmap - 22.12.2009 - Mindjet
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
non syndromic
syndromic
Figure 2
Rod > cone photoreceptor diseases
progressive
stationary
dominant
Night blindness:
GNAT1, PDE6B,
RHO
recessive
Incomplete night blindness:
CABP4, (CACNA2D4)
Complete night blindness:
GRM6, TRPM1
Oguchi disease:
SAG, GRK1
X-linked
Incomplete night blindness:
CACNA1F
Complete night blindness:
NYX
non syndromic
dominant
Retinitis pigmentosa:
BEST1, CA4, CRX,
FSCN2, GUCA1B,
IMPDH1, KLHL7,
NR2E3, NRL, PAP1,
PRPF3, PRPF8,
PRPF31, PRPH2,
RDH12, RGR, RHO,
ROM1, RP1, SEMA4A,
SNRNP200, TOPORS
recessive
Retinitis pigmentosa:
ABCA4, BEST1, CERKL,
CNGA1, CNGB1, CRB1,
EYS, LRAT, MERTK,
NR2E3, NRL, PDE6A,
PDE6B, PRCD, PROM1,
RBP3, RGR, RHO, RLBP1,
RP1, RPE65, SAG, TULP1,
USH2A
X-linked
Retinitis pigmentosa:
RP2 (semi-dominant and
recessive), RPGR
(dominant and recessive)
syndromic
recessive
Bardet Biedl syndrome:
BBS1, BBS2, BBS3, BBS4,
BBS5, BBS6, BBS7, BBS8,
BBS9, BBS10, BBS11,
BBS12, CEP290
Joubert syndrome:
AHL1, ARL13B,
CC2D2A, CEP290,
NPHP1, RPGRIP1L,
TMEM67, TMEM216
Primary ciliary dyskinesia (PCD):
DNAH5, DNAH11, DNAI1,
DNAI2, KTU, TXNDC3
Refsum disease:
PAHX, PEX1, PEX7,
PEX26, PXMP3
Senior Loken syndrome:
CEP290, NPHP1, NPHP2,
NPHP3, NPHP4, NPHP5
Usher syndrome:
CLRN1, CLRN3,
DFNB31, GPR98,
MYO7A, PCDH15,
SANS, USH1C, USH1D,
USH2A
X-linked
Joubert syndrome: OFD1
Retinitis pigmentosa with deafness
and sinorespiratory infections: RPGR
Figure_2.mmap - 16.02.2010 - Mindjet
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
Figure 3
Cone > rod photoreceptor diseases
progressive
stationary
dominant
Tritanopia: BCP
recessive
Complete achromatopsia:
CNGA3, CNGB3, GNAT2,
PDE6C
Incomplete achromatopsia:
CNGA3, GNAT2, PDE6C
non syndromic
dominant
AIPL1, CRX,
GUCA1A, GUCY2D,
HRG4/UNC119,
PITPNM3, PROM1,
PRPH2, RAX2, RIM1,
SEMA4A
recessive
Oligocone trichromacy:
CNGB3, GNAT2
X-linked
Blue cone monochromatism:
GCP, RCP
Macular degenerations (MDs)
Cone & cone rod dystrophies (CODs & CORDs)
ABCA4, ADAM9,
CACNA2D4, CNGA3,
KCNV2, PDE6C, PDE6H,
RDH5, RLBP1,
RPGRIP1, SEMA4A
syndromic
dominant
Neurofibromatosis 1: NF1
Spinocerebellar ataxia 7:
SCA7 (ATXN7)
recessive
Alström syndrome: ALMS1
Bardet Biedl syndrome : BBS1
CORD with
amelogenesis
imperfecta: CNNM4
non syndromic
dominant
BEST1, C1QTNF5,
CNGB3, EFEMP1,
ELOVL4, HMCN1,
FSCN2, GUCA1B,
PROM1, PRPH2,
TIMP3
syndromic
dominant
Spinocerebellar ataxia (SCA):
SCA7/ATXN7
recessive
Bardet Biedl syndrome : BBS1
recessive
Hypotrichosis with
juvenile MD: CDH3
ABCA4
X-linked
RPGR, RS1
X-linked
CACNA1F, RPGR
Figure_3.mmap - 26.02.2010 - Mindjet
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
Infantile Refsum disease:
PEX1, PEX26, PXMP3
Figure 4
Generalized photoreceptor diseases
progressive
non syndromic
dominant
Leber congenital amaurosis:
CRX, IMPDH1
recessive
Leber congenital amaurosis:
AIPL1, CEP290, CRB1, CRX,
GUCY2D, IMPDH1, LCA5,
LRAT, MERTK, RD3, RDH12,
RPE65, RPGRIP1, SPATA7,
TULP1
syndromic
dominant
Alagille syndrome:
JAG1, NOTCH2
recessive
Neuronal ceroid lipofuscinosis:
BTS, CLN5, CLN6, CLN7, CLN8,
CTSD, PPT1, TPP1
Refsum disease:
PAHX, PEX1, PEX7,
PEX26, PXMP3
Gyrate atrophy: OAT
X-linked
Choroideremia: CHM
Joubert syndrome:
AHL1, ARL13B,
CC2D2A, CEP290,
NPHP1, RPGRIP1L,
TMEM67, TMEM216
Senior Loken syndrome: CEP290
Figure_4.mmap - 26.02.2010 - Mindjet
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
Figure 5
Vitreoretinopathies (exudative and erosive)
progressive
non syndromic
dominant
Exudative vitroretinopathy
(EVR): FZD4 ( EVR1 ),
TSPAN12
Wagner disease
(WGN1): VCAN
Snowflake vitreoretinal
degeneration: KCNJ13
Vitreoretinal choroidopathy: BEST1
recessive
Exudative vitroretinopathy 4
(EVR4): LRP5
Enhanced S-cone syndrome, Goldmann
Favre syndrome (GFS): NR2E3
syndromic
dominant
Stickler syndrome 1
(STL1): COL2A1
Stickler syndrome 2
(STL2): COL11A1
Stickler syndrome 3
(STL3): COL11A2
recessive
Osteoporosis pseudoglioma
syndrome (OPPG): LRP5
Stickler syndrome (STL): COL9A1
X-linked
Norrie disease: NDP
X-linked
Exudative vitroretinopathy 2
(EVR2): NDP
Figure_5.mmap - 15.02.2010 - Mindjet
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
Figure 6
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
Table 1: Stationary photoreceptor diseases
Congenital stationary night blindness (CSNB)
Gene name
Calcium-binding protein 4
Voltage-dependent L-type calcium channel subunit
alpha-1F
Gene symbol
CABP4
CACNA1F
Gene symbol aliases
CSNB2B
CSNB2A, CORDX3,
Cav1.4, CSNB2A,
CSNBX2
Chromosome
11q13.1
Xp11.23
Inheritance
recessive
recessive
Ref.-seq.
NM_145200
NM_005183
Potential function
calcium signalling
Calcium channel
Additional phenotypes
incomplete CSNB, progressive
incomplete congenital stationary night blindness
Calcium channel, voltage-dependent, alpha 2/delta
subunit 4
CACNA2D4
RCD4
12p13.33
recessive
NM_172364
ion channel
incomplete CSNB, cone dystrophy (ar)
Guanine nucleotide-binding protein G(t) subunit
alpha-1
GNAT1
-
3p21.31
dominant
NM_144499
phototransduction
-
Rhodopsin kinase
Metabotropic glutamate receptor 6
GRK1
GRM6
GPRK1, RHOK, RK
CSNB1B, MGLUR6,
GPRC1F
13q34
5q35
recessive
recessive
NM_002929
NM_000843
phototransduction
glutamate transport
CSNB with fundus abnormalities
complete CSNB
Nyctalopin
Rod cGMP-specific 3',5'-cyclic phosphodiesterase
subunit beta
NYX
PDE6B
CSNB1A
PDEB, CSNB3, RP40
Xp11.4
4p16.13
recessive
dominant
NM_022567
NM_001145292
unknown
phototransduction
complete CSNB
retinitis pigmentosa
OPN2, RP4
LTRPC1, MLSN1
3q22.1
15q13.3
dominant
recessive
NM_000539
NM_002420
phototransduction
ion channel
retinitis pigmentosa
complete CSNB
RHO
Rhodopsin
Transient receptor potential cation channel subfamily TRPM1
M member 1
S-arrestin
SAG
Arrestin
2q37.1
recessive
NM_000541
phototransduction
CSNB with fundus abnormalities
Cone dysfunctions (stationary)
Gene name
Cyclic nucleotide-gated channel alpha-3 subunit
Gene symbol
CNGA3
Gene symbol aliases
ACHM2, CNCG3,
CCNCa, CNG3,
CCNC1
Chromosome
2q11.2
Inheritance
recessive
Ref.-seq.
NM_001298
Potential function
phototransduction
Additional phenotypes
complete or incomplete achromatopsia, typical or
atypical achromatopsia, rod monochromatism, cone
rod dystrophy (ar)
Cyclic nucleotide-gated cation channel beta-3
subunit
CNGB3
ACHM3
8q21.3
recessive
NM_019098
phototransduction
complete achromatopsia, typical achromatopsia, rod
monochromatism, macular degeneration
Guanine nucleotide-binding protein G(t) subunit
alpha-2
GNAT2
ACHM4
1p13.3
recessive
NM_005272
phototransduction
complete or incomplete achromatopsia, typical or
atypical achromatopsia, rod monochromatism,
oligocone trichromacy
Cone-specific phosphodiesterase alpha subunit
PDE6C
PDEA2
10q23.33
recessive
NM_006204
phototransduction
complete or incomplete achromatopsia, cone
dystrophy
Red cone photoreceptor pigment
RCP
OPN1LW, CBBM, CBP Xq28
recessive
NM_020061
phototransduction
blue cone monochromatism, X-linked atypical
achromatopsia, X-linked incomplete achromatopsia
Green cone photoreceptor pigment
GCP
OPN1MW, CBBM,
CBD, OPN1MW1
Xq28
recessive
NM_001048181
phototransduction
blue cone monochromatism, X-linked atypical
achromatopsia, X-linked incomplete achromatopsia
Blue cone photoreceptor pigment
OPN1SW
BCP, CBT
7q32.1
dominant
NM_001708
phototransduction
tritanopia
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information
Table_1.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
1
Table 2: Retinitis pigmentosa (RP)
Retinitis pigmentosa
Gene names
Carbonic anhydrase 4
Cone-rod homeobox protein
Gene symbol
CA4
CRX
Gene symbol aliases
RP17
CORD2, CRD, OTX3,
LCA7
Chromosome
17q23.2
19q13.32
Inheritance
dominant
dominant
Reference sequence
NM_000717
NM_000554
Potential function
unknown
transcription factor
Additional phenotype
cone rod dystrophy (ad), Leber congenital
amaurosis (ar and ad)
Fascin homolog 2
Guanylate cyclase activator 1B
Inosine monophosphate dehydrogenase 1
FSCN2
GUCA1B
IMPDH1
RP30
GCAP2
RP10, LCA11, MPD,
IMPD1,
17q25.3
6p21.1
7q32.1
dominant
dominant
dominant
NM_012418
NM_002098
NM_000883
cellular structure
phototransduction
regulation of cell growth
macular dystrophy (ad)
macular dystrophy (ad)
Leber congenital amaurosis (ad)
Kelch-like 7
KLHL7
RP42, SBBI26
7p15
dominant
NM_001031710
ubiquitin-proteasome protein degradation
Pim1 associated protein 1
Pre-mRNA processing factor 3 homolog
Pre-mRNA processing factor 31 homolog
Pre-mRNA processing factor 8 homolog
PAP1
PRPF3
PRPF31
PRPF8
RP9, PIM1K
RP18, HPRP3, PRP3
RP11, PRP31
RP13, PRPC8
7p14.3
1q21.2
19q13.42
17p13.3
dominant
dominant
dominant
dominant
NM_203288
NM_004698
NM_015629
NM_006445
splicing
splicing
splicing
splicing
Peripherin 2
PRPH2
RP7, RDS, TSPAN22,
rd2
6p21.1
dominant
NM_000322
photoreceptor outer segment macular dystrophy (ad), digenetic forms with
structure
ROM1, adult vitelliform macular dystrophy
(ad), pattern dystrophy
Retinol dehydrogenase 12
RDH12
LCA3, LCA13, SDR7C2,
FLJ30273
14q24.1
dominant
NM_152443
phototransduction
Leber congenital amaurosis (ar)
Retinal outer segment membrane protein 1
ROM1
RP7, ROSP1, TSPAN23
11q12.3
dominant
NM_000327
cellular structure
digenic forms with PRPH2
sema domain, immunoglobulin domain (Ig),
transmembrane domain (TM) and short
cytoplasmic domain, (semaphorin) 4A
SEMA4A
RP35, CORD10, SEMAB, 1q22
SemB
dominant
NM_022367
tissue development and
maintenance
cone rod dystrophy (ad)
Small nuclear ribonucleoprotein 200kDa (U5)
SNRNP200
BRR2, HELIC2,
ASCC3L1, U5-200KD
2q11.2
dominant
NM_014014
splicing
-
Topoisomerase I binding, arginine/serine-rich
TOPORS
RP31, LUN, P53BP3
9p21.1
dominant
NM_005802
-
-
Bestrophin-1
BEST1
VMD2, ARB, BMD,
TU15B,
11q12.3
dominant and
recessive
NM_004183
anion channel
autosomal dominant
vitreoretinochoroidopathy; Best macular
dystrophy (BMD) (ad)
Nuclear receptor subfamily 2, group E,
member 3
NR2E3
ESCS, PNR, RP37,
MGC49976, rd7, RNR
15q22.32
dominant and
recessive
NM_016346
transcription factor
enhanced S-cone syndrome (ar), GoldmannFavre syndrome
Neural retina leucine zipper
NRL
RP27
14q11.2
dominant and
recessive
NM_006177
tissue development and
maintenance
may include clumped pigmentary
degeneration and preserved blue cone
function
Retinal G protein coupled receptor
RGR
RP44
10q23.1
dominant and
recessive
NM_002921
retinal metabolism
choroidal sclerosis (ad)
Rhodopsin
RHO
RP4, OPN2
3q22.1
dominant and
recessive
NM_000539
phototransduction
CSNB (ad)
Retinitis pigmentosa 1
RP1
ORP1
8q12.1
dominant and
recessive
NM_006269
tissue development and
maintenance
-
Table_2.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
-
1
ATP-binding cassette, sub-family A member 4
ABCA4
RP19, ABCR, ARMD2,
CORD3, STGD1
1p22.1
recessive
NM_000350
transport
Stargardt disease, cone rod dystrophy,
juvenile and late onset macular
degeneration, fundus flavimaculatus; all (ar)
Ceramide kinase-like
CERKL
RP26
2q31.3
recessive
NM_001030311
tissue development and
maintenance
-
Cyclic nucleotide gated channel alpha 1
Cyclic nucleotide gated channel beta 1
CNGA1
CNGB1
CNCG, CNCG1
CNCG2, CNCG3L,
GAR1, GARP
4p12
16q13
recessive
recessive
NM_000087
NM_001297
phototransduction
phototransduction
-
Crumbs homolog 1
CRB1
RP12, LCA8, RP11,
1q31.3
recessive
NM_201253
tissue development and
maintenance
Leber congenital amaurosis (ar), pigmented
paravenous chorioretinal atrophy (ad),
retinitis pigmentosa (ar) with para-arteriolar
preservation of the RPE, sympotoms may
include Coats-like exudative vasculopathy
and thick retina with abnormal lamination
Eyes shut homolog
Lecithin retinol acyltransferase
C-mer proto-oncogene tyrosine kinase
Phosphodiesterase 6A
Phosphodiesterase 6B
Progressive rod-cone degeneration
Prominin 1
EYS
LRAT
MERTK
PDE6A
PDE6B
PRCD
PROM1
RP25, SPAM
MGC33103
RP38, MER, c-mer
RP43, CGPR-A
RP40, CSNB3
RP36
CORD12, CD133, RP41,
STGD4, AC133, MCDR2,
PROML1
6p12
4q32.1
2q14.1
5q33.1
4p16.3
17q25.1
4p15.32
recessive
recessive
recessive
recessive
recessive
recessive
recessive
NM_001142800
NM_004744
NM_006343
NM_000440
NM_000283
NM_001077620
NM_006017
retinal metabolism
transmembrane protein
phototransduction
phototransduction
cellular structure
Leber congenital amaurosis (ar)
LCA
CSNB (ad)
retinitis pigmentosa with macular
degeneration (ar); Stargardt-like macular
dystrophy (ad); macular dystrophy (ad); bull'seye; cone rod dystrophy (ad)
Retinol binding protein 3
Retinaldehyde binding protein 1
RBP3
RLBP1
IRBP
CRALBP
10q11.22
15q26.1
recessive
recessive
NM_002900
NM_000326
retinal metabolism
retinal metabolism
rod-cone dystrophy (ar), retinitis punctata
albescens (ar), Newfoundland rod cone
dystrophy (ar)
Retinal pigment epithelium-specific protein
65kDa
RPE65
RP20, LCA2
1p31.2
recessive
NM_000329
retinal metabolism
Leber congenital amaurosis (ar)
Arrestin, s-antigen
SAG
RP47, DKFZp686D1084, 2q37.1
DKFZp686I1383
recessive
NM_000541
phototransduction
Oguchi disease (ar)
Tubby like protein 1
TULP1
RP14, TUBL1
6p21.31
recessive
NM_003322
tissue development and
maintenance
Leber congenital amaurosis (ar)
Usher syndrome 2A
Retinitis pigmentosa 2
USH2A
RP2
RP39, USH2,
NME10, TBCCD2,
KIAA0215, DELXp11.3
1q41
Xp11.23
recessive
recessive
NM_206933
NM_006915
cellular structure
tissue development and
maintenance
Usher syndrome, type 2a (ar)
-
Retinitis pigmentosa GTPase regulator
RPGR
RP3, CORDX1, COD1,
CRD, RP15
Xp11.4
recessive
NM_000328
intraflagellar transport
cone rod dystrophy (Xl), atrophic macular
dystrophy (Xl), cone dystrophy (Xl)
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information
Table_2.xls
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Table 3: Non-syndromic and syndromic cone and cone rod dystrophies
Non-syndromic cone and cone rod dystrophies (COD, CORD, progressive)
Gene name
Gene symbol
Gene symbol aliases
ABCA4
CORD3, FFM, STGD1,
ATP-binding cassette sub-family A member 4
RP19, ABCR, STGD,
ARMD2
Chromosome
1p22.1
Inheritance
recessive
Ref.-seq.
NM_000350
Potential function
transport
Clinical diagnosis
Stargardt disease, retinitis pigmentosa, cone rod
dystrophy, juvenile and late onset macular degeneration,
fundus flavimaculatus; all (ar)
Metalloprotease disintegrin cysteine-rich protein
9
ADAM9
MDC9, MCMP
8p11.22
recessive
NM_003816
cell/matrix interaction
cone rod dystrophy
Aryl-hydrocarbon-interacting protein-like 1
AIPL1
LCA4, AIPL2
17p13.1
dominant
NM_014336
transport, protein
trafficking
cone rod dystrophy, Leber congenital amaurosis (ar)
Voltage-dependent L-type calcium channel
subunit alpha-1F
CACNA1F
CORDX3, CSNB2,
Cav1.4, CSNB2A,
CSNBX2
Xp11.23
recessive
NM_005183
Calcium channel
congenital stationary night blindness, cone rod dystrophy
Voltage-dependent calcium channel subunit
alpha-2/delta-4
CACNA2D4
RCD4
12p13.33
recessive
NM_172364
ion channel
cone dystrophy (ar), stationary night blindness (ar)
Cyclic nucleotide-gated cation channel beta-3
subunit
CNGA3
ACHM2, CNCG3,
CCNCa, CNG3, CCNC1
2q11.2
recessive
NM_001298
phototransduction
complete or incomplete achromatopsia, typical or atypical
achromatopsia, rod monochromatism, cone rod dystrophy
(ar)
Cellular retinaldehyde-binding protein
CRALBP
RLBP1
15q26.1
recessive
NM_000326
phototransduction
retinitis pigmentosa (ar), rod cone dystrophy (ar)
Cone-rod homeobox protein
CRX
CORD2, CRD, OTX3,
LCA7
19q13.32
dominant
NM_000554
transcription factor
cone rod dystrophy (ad), Leber congenital amaurosis (ad,
ar), retinitis pigmentosa (ad)
Guanylate cyclase activator 1A
GUCA1A
GCAP1, GUCA, GCAP,
GUCA1, COD3
6p21.1
dominant
NM_000409
phototransduction
cone dystrophy (ad) Color and central vision loss (ad)
Retinal guanylate cyclase 2D
GUCY2D
CORD6, GUC1A4,
17p13.1
GUC2D, LCA1, LCA,
retGC, CYGD, RETGC-1,
ROS-GC1, CORD5
dominant
NM_000180
phototransduction
Leber congenital amaurosis (ar)
Protein unc-119 homolog A, retinal protein 4
HRG4
UNC119
17q11.2
dominant
NM_005148
neurotransmitter release
cone rod dystrophy (ad)
Potassium voltage-gated channel subfamily V
member 2
KCNV2
Kv8.2, RCD3B
9p24.2
recessive
NM_133497
ion channel subunit
cone dystrophy with supernormal rod electroretinogram
Cone -specific phosphodiesterase alpha subunit
PDE6C
PDEA2
10q23.33
recessive
NM_006204
phototransduction
complete or incomplete achromatopsia, cone dystrophy
Retinal cone rhodopsin-sensitive cGMP 3',5'cyclic phosphodiesterase subunit gamma
PDE6H
RCD3A
12p12.3
recessive
NM_006205
phototransduction
cone dystrophy with supernormal rod electroretinogram
Membrane-associated phosphatidylinositol
transfer protein 3
PITPNM3
CORD5, NIR1, RDGBA3
17p13.2
dominant
NM_031220
transport
cone rod dystrophy
Prominin 1
PROM1
CORD12, CD133, RP41, 4p15.32
STGD4, AC133, MCDR2,
PROML1
dominant
NM_006017
cellular structure
Stargardt disease (ad), retinitis pigmentosa (ar), cone rod
dystrophy (ad), macular degeneration (ad)
Peripherin-2
PRPH2
RP7, RDS, TSPAN22, rd2 6p21.1
dominant
NM_000322
phototransduction
retinitis pigmentosa (ad, digenic with ROM1), macular
degeneration (ad)
Retina and anterior neural fold homeobox 2
RAX2
CORD11, RAXL1,
ARMD6, QRX
19p13.3
-
NM_032753
transcription
macular degeneration (isolated cases)
11-cis retinol dehydrogenase 5
RDH5
RDH1
12q13.2
recessive
NM_002905
chromophore metabolism late onset cone dystrophy (ar)
Table_3.xls
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Rab3-interacting molecule 1
RIM1
CORD7, RIMS1,
RAB3IP2, RIM
6q13
dominant
NM_014989
neurotransmitter release, cone rod dystrophy
exocytosis
Retinitis pigmentosa GTPase regulator
RPGR
CORDX1, COD1, RP3,
CRD, RP15
Xp11.4
recessive
and
dominant
NM_000328
intraflagellar transport
cone dystrophy, cone rod dystrophy, retinitis pigmentosa
(with deafness and sinorespiratory infections), macular
degeneration (Xlr, Xld)
Retinitis pigmentosa GTPase regulator
interacting protein 1
RPGRIP1
CORD13, RPGRIP, LCA6, 14q11.2
RGI1,RGRIP, RPGRIP1d
recessive
NM_020366
interaction with retinitis
pigmentosa GTPase
regulator protein
cone rod dystrophy, Leber congenital amaurosis (ar)
Sema domain, immunoglobulin domain (Ig),
transmembrane domain (TM) and short
cytoplasmic domain, (semaphorin) 4A
SEMA4A
CORD10, RP35, SEMAB, 1q22
SemB
recessive
and
dominant
NM_022367
axon guidance
cone rod dystrophy (ad, ar), retinitis pigmentosa (ad)
Chromos.
2p13
Inheritance
recessive
Ref.-seq.
NM_015120.4
Potential function
component of
centrosome and cilia
Clinical diagnosis
Alstrom syndrome (ar)
3p14.1
dominant
NM_001128149
potential transcription
factor
spinocerebellar ataxia (ad)
Syndromic cone and cone rod dystrophies (COD, CORD, progressive)
Gene name
Gene symbol
Gene symbol aliases
ALMS1
ALSS, DKFZp686A118,
Alstrom syndrome 1
DKFZp686D1828,
KIAA0328
Ataxin 7
ATXN7
ADCAII, OPCA3, SCA7
Bardet Biedl syndrome 1 gene
BBS1
BBS2L2, FLJ23590,
11q13.1
MGC51114, MGC126183,
MGC126184
recessive
NM_024649
centrosomal and ciliary
protein
retinitis pigmentos (ar), Bardet Biedl syndrome 1 (ar)
Cyclin M4
CNNM4
ACDP4, FLJ42791,
KIAA1592
recessive
NM_020184
potential metal
transporter
Jalli syndrome (ar)
Neurofibromin 1
NF1
FLJ21220, NFNS, VRNF, 17q11.2
WSS
dominant
NM_000267
tumor suppressor
neurofibromatosis (ad)
2q11.2
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information
Table_3.xls
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Table 4a: Non-syndromic and syndromic macular degenerations
Non-syndromic macular degenerations (MD), ARMD not included
Gene name
Gene symbol
ABCA4
Retinal-specific ATP-binding cassette
transporter (ATP-binding cassette sub-family A
member 4)
Bestrophin 1
BEST1
complement C1q tumor necrosis factor-related C1QTNF5
protein 5 precursor variant 3
Gene symbol aliases
CORD3, FFM, STGD1,
RP19, ABCR, STGD,
ARMD2
Chromososome
1p22.1
Inheritance
recessive
Ref.-seq.
NM_000350
Potential function
transport
Additional diagnosis
Stargardt disease (ar), retinitis pigmentosa (ar), cone rod
dystrophy (ar), juvenile and late onset macular
degeneration (ar), fundus flavimaculatus (ar)
VMD2, ARB, BMD,
TU15B,
11q12.3
dominant
NM_004183
anion channel
autosomal dominant vitreoretinochoroidopathy; Best
macular dystrophy (BMD) (ad)
CTRP5, LORD
11q23.3
dominant
NM_015645
small collagen
-
Cyclic nucleotide-gated cation channel beta-3
subunit
CNGB3
ACHM3
8q21.3
recessive
NM_019098
phototransduction
complete achromatopsia, typical achromatopsia, rod
monochromatism
Fibulin 3
EFEMP1
FBNL, 3218, DHRD, S15, FBLN3, MTLV
2p16.1
dominant
NM_004105
extracellular matrix
protein
Doyne honeycomb retinal degeneration
STGD3, STGD2
6q14.1
dominant
NM_022726
fatty acid metabolism
mutations in FSCN2 may cause RP
Elongation of very long chain fatty acids protein ELOVL4
4
Fascin homolog 2
FSCN2
RFSN, RP30
17q25.3
dominant
NM_012418
photoreceptor disk
morphogenesis
Guanylate cyclase activator 1B
Hemicentin 1
GUCA1B
HMCN1
GCAP2
ARMD1, FBLN6, FIBL-6,
FIBL6
6p21.1
1q31.1
dominant
dominant
NM_002098
NM_031935
phototransduction
retinitis pigmentosa (ad)
extracellular member of age-related macular degeneration
the immunoglobulin
superfamily
Prominin 1
PROM1
CORD12, CD133, RP41, 4p15.32
STGD4, AC133, MCDR2,
PROML1
dominant
NM_006017
cellular structure
Stargardt disease (ad), retinitis pigmentosa (ar), cone rod
dystrophy (ad)
Peripherin-2
PRPH2
RP7, RDS, TSPAN22,
rd2
6p21.1
dominant
NM_000322
photoreceptor outer
segment structure
cone dystrophy, cone rod dystrophy, retinitis pigmentosa
(ad, digenic with ROM1),
Retinitis pigmentosa GTPase regulator
RPGR
CORDX1, COD1, RP3,
CRD, RP15
Xp11.4
recessive
NM_000328
and dominant
intraflagellar transport
cone dystrophy, cone rod dystrophy, retinitis pigmentosa
(with deafness and sinorespiratory infections), macular
degeneration (Xlr, Xld)
Retinoschisin
Tissue inhibitor of metalloproteinases 3
RS1
TIMP3
RS, XLRS1
SFD
Xp22.13
22q12.3
recessive
dominant
NM_000330
NM_000362
adhesion molecule?
ECM remodelling?
Sorsby fundus dystrophy (ad)
Gene name
Ataxin 7
Gene symbol
ATXN7
Gene symbol aliases
ADCAII, OPCA3, SCA7
Chromosome
3p14.1
Inheritance
dominant
Ref.-seq.
NM_001128149
Potential function
potential transcription
factor
Additional diagnosis
spinocerebellar ataxia (ad)
Bardet Biedl syndrome 1 gene
BBS1
BBS2L2, FLJ23590,
11q13.1
MGC51114, MGC126183,
MGC126184
recessive
NM_024649
centrosomal and ciliary retinitis pigmentos (ar), Bardet Biedl syndrome 1 (ar)
protein
Peroxisomal biogenesis factor 1
PEX1
IRD
7q21.2
recessive
NM_000466
peroxisomal protein
import
infantile form of phytanic acid storage disease
Peroxisomal biogenesis factor 26
PEX26
PEX26M1T, Pex26pM1T
22q11.21
recessive
NM_017929
peroxisomal protein
import
infantile form of phytanic acid storage disease
Peroxisomal membrane protein 3
PXMP3
PEX2, PMP35, PAF-1
8q21.11
recessive
NM_000318
peroxisome biogenesis infantile form of phytanic acid storage disease
Syndromic macular degenerations (MD)
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information
Table_4a.xls
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Table 4b: Age-related macular degeneration
AMD associated genes
Gene name
ATP-binding cassette sub-family A member 4
Gene symbol
ABCA4
Gene symbol aliases
ARMD2, ABCR, CORD3, FFM,
RP19, STGD, STGD1
Chromosome
1p22.1
Ref.-Seq.
NM_000350
Potential function
transport
Additional diagnosis
Stargardt disease, retinitis pigmentosa, cone rod
dystrophy, juvenile and late onset macular
degeneration, fundus flavimaculatus; all (ar)
Apolipoprotein E
APOE
AD2, LDLCQ5, LPG, MGC1571
19q13.2
NM_000041
catabolism of triglyceride-rich lipoprotein
familial dysbetalipoproteinemia (ad and ar), or type III
hyperlipoproteinemia (HLP III) (ar and ad), end-stage
renal disease (ESRD)(ad), Susceptibility to Alzheimer's
disease
Age-related maculopathy susceptibility 2
Complement component 2
ARMS2
C2
10q26.13
6p21.3
NM_001099667
NM_000063
mitochondrial outer membrane protein
classical pathway of complement system
-
Complement component 3
Complement factor B
C3
CFB
ARMD8
DADB-122G4.1, CO2,
DKFZp779M0311
ARMD9, ASP, CPAMD1
DADB-122G4.5, BF, BFD, CFAB,
FB, FBI12, GBG, H2-Bf, PBF2
19p13.3
6p21.3
NM_001735
NM_001710
activation of complement system
immune system; complement and coagulation
cascades
Susceptibility to bacterial infection
-
Complement factor H
CFH
1q32
NM_000186
atypical hemolytic uremic syndrome
20p11.21
10q11.23
NM_000099
NM_000124
immune system; complement and coagulation
cascades
extracellular inhibitor of cysteine proteases
DNA repair
amyloid angiopathy AMD
Cockayne syndrome type B (ar)
14q32.1
NM_006329
vascular development and remodeling
autosomal dominant cutis laxa, cutis laxa type I (ar)
1q31.1
NM_031935
extracellular member of the immunoglobulin
superfamily
regulation of availability of insulin-like growth
factors; regulator of cell growth
mediators of inflammatory response;
chemoattractant; angiogenic factor
macular deheneration (ad)
CST3
Cystatin C
Excision repair cross-complementing rodent repair ERCC6
deficiency
FBLN5
Fibulin 5
Hemicentin 1
HMCN1
HtrA serine peptidase 1
HTRA1
Interleukin 8
ARMD4, ARMS1, CFHL3, HUS,
MGC88246
ARMD11, MGC117328
ARMD5, CKN2, COFS, COFS1,
CSB, RAD26
ARMD3, DANCE, EVEC, FIBL-5,
FLJ90059, UP50
ARMD1,FBLN6, FIBL-6, FIBL6
IL-8
ARMD7, HtrA, L56, ORF480,
10q26.3
PRSS11
CXCL8, GCP-1, GCP1, LECT,
4q13-q21
LUCT, LYNAP, MDNCF, MONAP,
NAF, NAP-1, NAP1
NM_000634
Pleckstrin homology domain containing, family A
PLEKHA1
TAPP1
10q26.13
NM_021622
-
-
Paraoxonase 1
PON1
ESA, PON
7q21.3
NM_000446
arylesterase
retina and anterior neural fold homeobox 2
RAX2
ARMD6, CORD11, QRX, RAXL1
19p13.3
NM_032753
transcription
risk factor in coronary artery disease and amylotrophic
lateral sclerosis (ALS)
cone-rod dystrophy type 11
Serpin peptidase inhibitor, clade G (C1 inhibitor),
member 1
Toll-like receptor 3
SERPING1
11q12
NM_000062
regulation of the complement cascade
hereditary angioneurotic oedema (HANE) (ar)
TLR3
C1IN, C1INH, C1NH, HAE1,
HAE2
CD283
4q35
NM_003265
-
Toll-like receptor 4
Vascular endothelial growth factor A
TLR4
VEGFA
9q32
6p12
NM_138554
NM_001025366
pathogen recognition and activation of innate
immunity
innate immune system
vascular permeability, angiogenesis,
vasculogenesis and endothelial cell growth, cell
migration, apoptosis
ARMD10, CD284, TOLL, hToll
RP1-261G23.1, MGC70609,
MVCD1, VEGF, VEGF-A, VPF
NM_002775
-
lipopolysaccharide responsiveness
diabetic retinopathy
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information
Table_4b.xls
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Table 5: Non-syndromic and syndromic generalized photoreceptor diseases
Leber congenital amaurosis (LCAs)
Gene name
Gene symbol
Gene symbol aliases
AIPL1
LCA4, AIPL2
Aryl-hydrocarbon-interacting protein-like 1
Chromosome
17p13.1
Inheritance
recessive
Ref.-seq.
NM_014336
Potential function
protein-protein interaction
Additional diagnosis
cone rod dystrophy (ad)
Centrosomal protein 290
CEP290
LCA10, SLSN6, MKS4,
JBTS5, BBS14, NPHP6
12q21.32
recessive
NM_025114
centrosomal and ciliary
protein
Senior Loken syndrome type 6 (ar), Meckel syndrome
type 4 (ar), Joubert syndrome type 5 (ar), Bardet Biedl
syndrome type 14 (ar)
Crumbs homolog 1
CRB1
LCA8, RP11, RP12
1q31.3
recessive
NM_201253
tissue development and
maintenance
severe retinitis pigmentosa (ar), pigmented
paravenous chorioretinal atrophy (ad),
Cone-rod homeobox protein
CRX
LCA7, CORD2, CRD,
OTX3
19q13.32
recessive
and rarely
dominant
NM_000554
transcription factor
cone rod dystrophy (ad), retinitis pigmentosa (ad)
Retinal guanylate cyclase 2D
GUCY2D
LCA1, CORD6, GUC1A4,
GUC2D, LCA, retGC,
CYGD, RETGC-1, ROSGC1, CORD5
17p13.1
recessive
NM_000180
phototransduction
cone rod dystrophy (ad)
Inosine monophosphate dehydrogenase 1
IMPDH1
LCA11, IMPD, IMPD1,
RP10
7q32.1
recessive
and rarely
dominant
NM_000883
regulation of cell growth
retinitis pigmentosa (ad)
Leber congenital amaurosis 5
LCA5
LCA5, C6ORF152,
Lebercillin
6q14.1
recessive
NM_181714
centrosomal protein with
ciliary function
-
Lecithin retinol acyltransferase
C-mer proto-oncogene tyrosine kinase
Retinal degeneration 3
Retinol dehydrogenase 12
LRAT
MERTK
RD3
RDH12
MGC33103
MER, RP38, c-mer
LCA12, C1ORF36
FLJ30273, LCA3, LCA13,
SDR7C2
4q32.1
2q14.1
1q32.3
14q24.1
recessive
recessive
recessive
recessive
NM_004744
NM_006343
NM_183059
NM_152443
retinal metabolism
transmembrane protein
transcription and splicing
phototransduction
early-onset severe retinal dystrophy (ar)
retinitis pigmentosa (ar)
retinitis pigmentosa (ad)
Retinal pigment epithelium-specific protein
65kDa
RPE65
LCA2, RP20,
1p31.2
recessive
NM_000329
visual cycle
retinitis pigmentosa (ar)
Retinitis pigmentosa GTPase regulator
interacting protein 1
RPGRIP1
LCA6, CORD13, RGI1,
RGRIP, RPGRIP,
RPGRIP1d
14q11.2
recessive
NM_020366
interaction with retinitis
pigmentosa GTPase
regulator protein
congenital blindness, cone rod dystrophy (ar)
Spermatogenesis associated 7
Tubby like protein 1
SPATA7
TULP1
HSD-3.1, HSD3, LCA3
RP14, TUBL1
14q31.3
6p21.31
recessive
recessive
NM_018418
NM_003322
tissue development and
maintenance
juvenile retinitis pigmentosa (ar)
retinitis pigmentosa (ar)
Gyrate atrophy
Gene name
Ornithine aminotransferase
Gene symbol
OAT
Gene symbol aliases
HOGA
Chromosome
10q26.13
Inheritance
recessive
Ref.-seq.
NM_000274
Potential function
Additional diagnosis
neurotransmitter metabolism -
Choroideremia
Gene name
Choroideremia protein
Gene symbol
CHM
Gene symbol aliases
TCD, REP-1
Chromosome
Xq21.2
Inheritance
recessive
Ref.-seq.
NM_000390
Potential function
protein prenylation
Alagille syndrome
Gene name
Jagged1
Gene symbol
JAG1
Gene symbol aliases
AGS
Chromosome
20p12.2
Inheritance
dominant
Ref.-seq.
NM_000214
Potential function
Additional diagnosis
development, notch signalling -
Notch 2 receptor
NOTCH2
hN2, AGS2
1p12
dominant
NM_024408
development, notch signalling -
Additional diagnosis
-
Neuronal ceroid lipofuscinosis (CLN), Batten disease
Table_5_incl_syndromic.xls
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Gene name
Battenin, Batten disease protein
Ceroid-lipofuscinosis neuronal protein 5
Ceroid-lipofuscinosis neuronal protein 6
Ceroid-lipofuscinosis neuronal protein 7
Ceroid-lipofuscinosis neuronal protein 8
Cathepsin D
Palmitoyl-protein hydrolase 1
Tripeptidyl-peptidase 1
Gene symbol
BTS
CLN5
CLN6
CLN7
CLN8
CTSD
PPT1
TPP1
Gene symbol aliases
CLN3, JNCL
MFSD8
CLN10, CPSD
CLN1, PPT
CLN2
Chromosome
16p12.1
13q22.3
15q23
4q28.2
8p23
11p15.5
1p34.2
11p15.4
Inheritance
recessive
recessive
recessive
recessive
recessive
recessive
recessive
recessive
Ref.-seq.
NM_000086
NM_006493
NM_017882
NM_152778
NM_018941
NM_001909
NM_000310
NM_000391
Potential function
lysosomal protein
unknown
unknown
lysosomal transporter
ER / Glogi protein
intracellular protease
lysosomal degradation
lysosomal protease
Additional diagnosis
macular degeneration, retinal degeneration
-
Gene name
Phytanoyl-CoA 2-hydroxylase
Gene symbol
PAHX
Gene symbol aliases
PHYH, PHYH1
Chromosome
10p13
Inheritance
recessive
Ref.-seq.
NM_001037537
Potential function
peroxisomal fatty acid
oxidation
Additional diagnosis
-
Peroxisome biogenesis factor 1
Peroxisome assembly protein 26
PEX1
PEX26
IRD
FLJ20695, PEX26M1T,
Pex26pM1T
7q21.2
22q11.21
recessive
recessive
NM_000466
NM_017929
peroxisomal protein import
peroxisomal protein import
-
Peroxisomal targeting signal 2 receptor
peroxisomal membrane protein 3
PEX7
PXMP3
PTS2R
PEX2, PMP35, PAF-1
6q23.3
8q21.11
recessive
recessive
NM_000288
NM_000318
peroxisome biogenesis
peroxisome biogenesis
infantile form of phytanic acid storage disease
Joubert syndrome
Gene name
Abelson helper integration1
ADP-ribosylation factor-like 13B
Coiled-coil and C2 domain containing 2A
Gene symbol
AHL1
ARL13B
CC2D2A
Gene symbol aliases
JBTS3; ORF1; AHI-1
JBTS8, ARL2L1
JBTS9, KIAA1345, MKS6
Chromosome
6q23.3
3q11.2
4p15.33
Inheritance
recessive
recessive
recessive
Ref.-seq.
NM_017651
NM_182896
NM_001080522
Potential function
ciliary function
interaction with protein
CEP290
Additional diagnosis
mental retardation with retinitis pigmentosa (ar)
Centrosomal protein 290
CEP290
LCA10, SLSN6, MKS4,
JBTS5, BBS14, NPHP6
12q21.32
recessive
NM_025114
centrosomal and ciliary
protein
Senior Loken syndrome type 6 (ar), Meckel syndrome
type 4 (ar), Bardet Biedl syndrome type 14 (ar), Leber
congenital amaurosis type 10 (ar)
Nephronophthisis 1
NPHP1
JBTS4, SLSN1
2q13
recessive
NM_000272
control of cell division, cellcell and cell-matrix adhesion
signaling, complex in actinand microtubule-based
structures
Oral-facial-digital syndrome 1
OFD1
JBTS10
Xp22
recessive
NM_003611
interacts with LCA5-encoded lebercilin
RPGR-interacting protein 1-like protein
RPGRIP1L
JBTS7, KIAA1005, MKS5,
NPHP8
16q12.2
recessive
NM_015272
localization to centrosome
and primary cilia
Meckel syndrome (ar)
Transmembrane protein 67
Transmembrane protein 216
TMEM67
TMEM216
JBTS6, MKS3,
JBTS2
8q24
11q12.2
recessive
recessive
NM_153704
NM_016499
ciliary function
-
Meckel syndrome (ar)
Senior Loken syndrome
Gene name
Centrosomal protein 290
Gene symbol
CEP290
Gene symbol aliases
LCA10, SLSN6, MKS4,
JBTS5, BBS14, NPHP6
Chromosome
12q21.32
Inheritance
recessive
Ref.-seq.
NM_025114
Potential function
centrosomal and ciliary
protein
Additional diagnosis
Joubert syndrome 5 (ar), Meckel syndrome type 4 (ar),
Bardet Biedl syndrome type 14 (ar), Leber congenital
amaurosis type 10 (ar)
Refsum disease
Table_5_incl_syndromic.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
2
Nephrocystin 1
NPHP1
SLSN1, JBTS4
2q13
recessive
NM_000272
cell division, adhesion
Nephronophthisis (ar), Joubert syndrome type 4 (ar)
Nephrocystin 2
Nephrocystin 3
Nephrocystin 4, Nephroretinin
Nephrocystin 5
NPHP2
NPHP3
NPHP4
NPHP5
INVS, inversin
SLSN3
SLSN4
SLSN5, IQCB1
9q31
3q22.1
1p36.31
3q13.33
recessive
recessive
recessive
recessive
NM_183245
NM_153240
NM_015102
NM_001023570
cell cycle
unknown
unknown
unknown
Nephronophthisis (ar)
Nephronophthisis (ar)
Nephronophthisis (ar)
Nephronophthisis (ar)
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information available
Table_5_incl_syndromic.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
3
Table 6: Exudative and erosive vitreoretinopathies
Non-syndromic exudative vitreoretinopathies (EVR)
Gene name
Gene symbol
FZD4
Frizzled-4
LRP5
Low-density lipoprotein receptor-related protein 5
Gene symbol aliases
EVR1, CD344
EVR4, OPPG, OPS,
LR3, BMND1
Chromosome
11q14.2
11q13.2
Inheritance
dominant
recessive
Ref.-seq.
NM_012193
NM_002335
Potential function
Wnt signalling
Wnt signalling
Additional diagnosis
Osteoporosis pseudoglioma syndrome (OPPG, ar),
osteoporosis (ad), bone mineral density quantitative
trait locus
Norrin
NDP
EVR2
Xp11.3
X-linked
recessive
NM_000266
Ligand of FZD4 and
LRP5
Norrie disease pseudoglioma (Xlr), retinopathy of
prematurity (ROP)
Tetraspanin 12
TSPAN12
TM4SF12, NET-2
7q31.31
dominant
NM_012338
Norrin-coreceptor
-
Non-syndromic erosive vitreoretinopathies (ERVR)
Gene name
Bestrophin 1
Gene symbol
BEST1
Gene symbol aliases
VMD2, ARB, BMD,
TU15B,
Chromosome
11q12.3
Inheritance
dominant
Ref.-seq.
NM_004183
Potential function
anion channel
Additional diagnosis
autosomal dominant vitreoretinochoroidopathy; Best
macular dystrophy (BMD) (ad)
Potassium inwardly-rectifying channel
KCNJ13
KIR1.4, KIR7.1,
MGC33328, SVD
2q37
dominant
NM_002242
potassium channels
snowflake vitreoretinal degeneration (SVD) (ad)
Nuclear receptor subfamily 2, group E, member 3
NR2E3
ESCS, MGC49976,
PNR, RNR, RP37, rd7
15q22.32
dominant
NM_016346
transcription factor
enhanced S cone syndrome (ESCS) (ad and ar);
retinitis pigmentosa type 37 (ad); Goldmann-Favre
Syndrome
Versican
VCAN
CSPG2, ERVR, PG-M,
WGN, WGN1
5q14.3
dominant
NM_004385
hyaluronic acid binding,
extracellular matrix
Wagner syndrome 1, ERVR (ad)
Syndromic Vitreoretinopathies
Stickler syndrome
Gene name
Collagen, type II, alpha 1
Gene symbol
COL2A1
Gene symbol aliases
ANFH, AOM,
COL11A3,
MGC131516, SEDC
Chromosome
12q13.11
Inheritance
dominant
Ref.-seq.
NM_001844
Potential function
extracellular matrix
Additional diagnosis
achondrogenesis, chondrodysplasia, early onset
familial osteoarthritis, SED congenita, Langer-Saldino
achondrogenesis, Kniest dysplasia, and
spondyloepimetaphyseal dysplasia Strudwick type (ad
and ar)
Collagen, type XI, alpha 1
COL11A1
CO11A1, COLL6, STL2 1p21
dominant
NM_001854
extracellular matrix
Marshall syndrome (ad)
Collagen, type XI, alpha 2
COL11A2
DADB-100D22.2,
DFNA13, DFNB53,
HKE5, PARP, STL3
6p21.3
dominant
NM_080680
extracellular matrix
otospondylomega-epiphyseal dysplasia (OSMED
syndrome) (ad), Weissenbacher-Zweymuller
syndrome (ar), non-syndromic sensorineural type 13
deafness (DFNA13) (ad), non-syndromic
sensorineural type 53 deafness (DFNB53) (ar)
Collagen, type IX, alpha 1
COL9A1
RP1-138F4.2,
DJ149L1.1.2, EDM6,
FLJ40263, MED
6q12-q14
recessive
NM_001851
structural association with collagen type II and XI
Norrie disease pseudoglioma
Gene name
Norrin
Gene symbol
NDP
Gene symbol aliases
EVR2
Chromosome
Xp11.3
Inheritance
X-linked
recessive
Ref.-seq.
NM_000266
Potential function
Ligand of FZD4 and
LRP5
Table_6.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
Additional diagnosis
Norrie disease pseudoglioma (Xlr), retinopathy of
prematurity (ROP)
1
Osteoporosis pseudoglioma syndrome
Gene name
Low-density lipoprotein receptor-related protein 5
Gene symbol
LRP5
Gene symbol aliases
EVR4, OPPG, OPS,
LR3, BMND1
Chromosome
11q13.2
Inheritance
recessive
Ref.-seq.
NM_002335
Potential function
Wnt signalling
Additional diagnosis
Osteoporosis pseudoglioma syndrome (OPPG, ar),
osteoporosis (ad), bone mineral density quantitative
trait locus
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information available
Table_6.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
2
Table 8: Syndromic, rod dominated retinal degenerations
Bardet Biedl syndrome
Gene name
Gene symbol
BBS1
Bardet Biedl Syndrome gene 1
Gene symbol aliases
BBS2L2, FLJ23590,
MGC51114,
MGC126183,
MGC126184
Chromosome
11q13.1
Inheritance
recessive
Ref.-seq.
NM_024649
Potential function
centrosomal and ciliary
protein
additional phenotype
retinitis pigmentosa (ar), macular degeneration (ar),
cone rod dystrophy (ar)
Bardet Biedl Syndrome gene 2
BBS2
MGC20703
16q13
recessive
NM_031885
cilia formation and function
-
Bardet Biedl Syndrome gene 3
Bardet Biedl Syndrome gene 4
BBS3
BBS4
ARL6
-
3q11.2
15q24.1
recessive
recessive
NM_032146
NM_033028
ciliary transport
basal bodies and cetriolar
statelites
-
Bardet Biedl Syndrome gene 5
Bardet Biedl Syndrome gene 6
BBS5
BBS6
MKKS, HMCS, KMS,
MKS
2q31.1
20p12.2
recessive
recessive
NM_152384
NM_018848
basal bodies
protein folding
McKusick-Kaufmann syndrome (ar)
Bardet Biedl Syndrome gene 7
BBS7
BBS2L1, FLJ10715
4q27
recessive
NM_176824
cilia formation and function
-
Bardet Biedl Syndrome gene 8
BBS8
TTC8
14q31.3
recessive
NM_144596
basal bodies and
centrosomes
-
Bardet Biedl Syndrome gene 9
BBS9
PTHB1, MGC118917
7p14.3
recessive
NM_198428
cilia formation and function
-
Bardet Biedl Syndrome gene 10
Bardet Biedl Syndrome gene 11
BBS10
BBS11
C12orf58, FLJ23560
12q21.2
TRIM32, HT2A, TATIP, 9q33.1
LGMD2H
recessive
recessive
NM_024685
NM_012210
protein folding
proteasome degradation
-
Bardet Biedl Syndrome gene 12
BBS12
C4orf24, FLJ35630,
FLJ41559
recessive
NM_152618
protein folding
-
Bardet Biedl Syndrome gene 14
CEP290
BBS14, LCA10,
12q21.32
SLSN6, MKS4, JBTS5,
NPHP6
recessive
NM_025114
centrosomal and ciliary
protein
Senior Loken syndrome (ar), Meckel syndrome (ar),
Joubert syndrome (ar), LCA (ar)
Joubert syndrome
Gene name
Abelson helper integration1
Gene symbol
AHL1
Gene symbol aliases
JBTS3; ORF1; AHI-1
Chromosome
6q23.3
Inheritance
recessive
Ref.-seq.
NM_017651
Potential function
-
Additional diagnosis
-
ADP-ribosylation factor-like 13B
Coiled-coil and C2 domain containing 2A
ARL13B
CC2D2A
JBTS8, ARL2L1
JBTS9, KIAA1345,
MKS6
3q11.2
4p15.33
recessive
recessive
NM_182896
NM_001080522
ciliary function
interaction with protein
CEP290
mental retardation with retinitis pigmentosa (ar)
Centrosomal protein 290
CEP290
JBTS5, BBS14, LCA10, 12q21.32
MKS4, NPHP6, SLSN6
recessive
NM_025114
localized to centrosome and Senior Loken syndrome type 6 (ar), Leber congenital
cilia, interaction with protein amaurosis (LCA10, ar), Meckel syndrome type 4
(ar),Bardet Biedl syndrome 14 (ar)
CC2D2A
Nephronophthisis 1
NPHP1
JBTS4, SLSN1
recessive
NM_000272
control of cell division, cellcell and cell-matrix adhesion
signaling, complex in actinand microtubule-based
structures
Table_8.xls
4q27
2q13
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
1
Oral-facial-digital syndrome 1
OFD1
JBTS10
Xp22
recessive
NM_003611
interacts with LCA5-encoded lebercilin
RPGR-interacting protein 1-like protein
RPGRIP1L
JBTS7, KIAA1005,
MKS5, NPHP8
16q12.2
recessive
NM_015272
localization to centrosome
and primary cilia
Meckel syndrome (ar)
Transmembrane protein 67
Transmembrane protein 216
TMEM67
TMEM216
JBTS6, MKS3,
HSPC244
8q24
11q12.2
recessive
recessive
NM_153704
NM_016499
ciliary function
ciliary function
Meckel syndrome (ar)
-
Primary ciliary dyskinesias (PCD)
Gene name
Axonemal dynein heavy chain 11
Gene symbol
DNAH11
Gene symbol aliases
DPL11, DNAHC11,
2942, DNAHBL,
DNHBL, CILD7
Chromososome
7p15.3
Inheritance
recessive
Ref.-seq.
NM_003777
Potential function
motor ATPase
Additional diagnosis
-
Axonemal dynein heavy chain 5
DNAH5
HL1, KTGNR, 2950,
DNAHC5, CILD3, PCD
5p15.2
recessive
NM_001369
-
Axonemal dynein intermediate chain 1
Axonemal dynein intermediate chain 2
Kintoun
DNAI1
DNAI2
KTU
CILD1, PCD
CILD9
C14orf104, 20188,
FLJ10563
9p13.3
17q25.1
14q22.1
recessive
recessive
recessive
NM_012144
NM_023036
NM_018139
-
Thioredoxin domain-containing protein 3
TXNDC3
CILD6, NME8, SPTRX2 7p14.1
recessive
NM_016616
protein disulfide reductase
-
Gene name
Phytanoyl-CoA 2-hydroxylase
Gene symbol
PAHX
Gene symbol aliases
PHYH, PHYH1
Chromososome
10p13
Inheritance
recessive
Ref.-seq.
NM_001037537
Potential function
peroxisomal fatty acid
oxidation
Additional diagnosis
adult form
Peroxisomal biogenesis factor 1
PEX1
IRD
7q21.2
recessive
NM_000466
peroxisomal protein import
infantile form of phytanic acid storage disease
Peroxisomal targeting signal 2 receptor
peroxisomal biogenesis factor 26
PEX7
PEX26
PTS2R
PEX26M1T,
Pex26pM1T
6q23.3
22q11.21
recessive
recessive
NM_000288
NM_017929
peroxisome biogenesis
peroxisomal protein import
adult form
infantile form of phytanic acid storage disease
Peroxisome assembly factor 1 (PAF-1),
Peroxin-2
PXMP3
PEX2, PMP35, PAF-1
8q21.11
recessive
NM_000318
peroxisome biogenesis
infantile form of phytanic acid storage disease
Senior Loken syndrome
Gene name
Centrosomal protein 290
Gene symbol
CEP290
Gene symbol aliases
Chromososome
SLSN6, MKS4, JBTS5, 12q21.32
NPHP6, BBS14, LCA10
Inheritance
recessive
Ref.-seq.
NM_025114
Potential function
centrosomal and ciliary
protein
Additional diagnosis
Leber congenital amaurosis (LCA10, ar), Meckel
syndrome type 4 (ar), Joubert syndrome 5 (ar), Bardet
Biedl syndrome 14 (ar)
Nephrocystin 1
NPHP1
SLSN1, JBTS4
2q13
recessive
NM_000272
cell division, adhesion
Nephronophthisis (ar), Joubert syndrome type 4 (ar)
Nephrocystin 2
Nephrocystin 3
Nephrocystin 4, Nephroretinin
Nephrocystin 5
NPHP2
NPHP3
NPHP4
NPHP5
INVS
SLSN3
SLSN4
SLSN5, IQCB1
9q31
3q22.1
1p36.31
3q13.33
recessive
recessive
recessive
recessive
NM_183245
NM_153240
NM_015102
NM_001023570
cell cycle
-
Nephronophthisis (ar)
Nephronophthisis (ar)
Nephronophthisis (ar)
Nephronophthisis (ar)
Refsum disease
Table_8.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
2
Usher syndrome (USH)
Gene name
Clarin-1
Clarin-3
Deafness, autosomal recessive 31
Gene symbol
CLRN1
CLRN3
DFNB31
Gene symbol aliases
USH3A
USH3AL1, TMEM12
USH2D, CIP98, WHRN,
DFNB31
G-protein coupled receptor 98
GPR98
Myosin-VIIa
Chromososome
3q25.1
10q26.2
9q32
Inheritance
recessive
recessive
recessive
Ref.-seq.
NM_052995
NM_152311
NM_001083885
Potential function
ribbon synapse?
-
Additional diagnosis
deafness (ar)
USH2C, FEB4, MASS1, 5q14.3
VLGR1b
recessive
NM_032119
-
-
MYO7A
USH1B, NSRD2,
DFNA11, DFNB2
11q13.5
recessive
NM_000260
vesicle trafficking, transport
deafness (ar)
Protocadherin-15
PCDH15
USH1F, DFNB23
10q21.1
recessive
NM_001142764
cell adhesion
deafness (ar), digenic Usher syndrome with CDH23
Usher syndrome type-1G protein
Harmonin
SANS
USH1C
USH1G, ANKS4A
AIE-75, PDZ73, PDZ73, DFNB18
17q25.1
11p15.1
recessive
recessive
NM_173477
NM_005709
scaffold protein
-
deafness (ar)
Cadherin-23 Precursor, Otocadherin
USH1D
CDH23, DFNB12
10q22.1
recessive
NM_052836
cell adhesion
deafness (ar), digenic Usher syndrome with PCDH15
Usher syndrome 2A
USH2A
USH2, RP39
1q41
recessive
NM_206933
cellular structure
retinitis pigmentosa (ar)
For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information available
Table_8.xls
12.03.2010
Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)
3