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BritishJournal ofOphthalmology 1993; 77: 469-470
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Editorials
Hereditary retinopathies: insights into a complex genetic aetiology
Retinitis pigmentosa (RP), a disease currently affecting an
estimated 1-5 million people throughout the world, is the
most prevalent human retinopathy displaying clear cut
hereditary tendencies - that is, the disease may segregate in
an autosomal dominant, in a recessive, or in an X linked
fashion. Until recently the cause of the condition in humans
remained obscure. However, the fact that the disease segregates according to strict Mendelian ratios indicates that in any
given pedigree a single defective gene is involved, a major
ongoing challenge of human molecular genetics lying in the
isolation and characterisation of such genes. With a genome
consisting of some three billion base pairs of DNA and
probably between 50000 and 100 000 genes, the task of
locating a single disease-causing gene, particularly when the
biochemical defect is unknown, would seem, to say the least,
daunting. Nevertheless for RP (and indeed a growing
number of other prevalent Mendelian disorders) much
progress has been made over the last few years. Work on
localising disease genes has been facilitated by an exponentially expanding human genetic map and, in the case of RP,
the availability of many large families with the disease. The
technique of genetic linkage analysis has been widely
employed in the search for such genes. Using this technique,
DNA isolated from family members is screened with a large
bank of genetic markers. Eventually, through a process of
trial and error, a linkage between the disease phenotype and a
particular genetic marker is established.
This methodology was first used successfully back in the
1950s for the localisation of the gene which causes myotonic
dystrophy and while, in principle, the method was highly
effective an insufficient number of informative genetic
markers was available to make the methodology routinely
feasible. This changed in the mid to late 1970s when genetic
markers based on polymorphism at the level of the DNA
sequence itself (so-called restriction fragment length polymorphisms or RFLPs) were developed. More recently, a new
generation of DNA markers has been developed through the
use of the polymerase chain reaction. Such markers, often
referred to as 'microsatellites' are based on polymorphism in
the numbers of short tandemly repeated DNA sequences
(STRs) at a given locus. DNA across the variable region is
amplified, and length variation can usually be detected. With
such markers the task of localising disease-causing genes has
become much more readily achievable.
The first progress to be made in localising an RP-causing
gene came from the work of Bhattacharya and colleagues in
1984.' These workers were able to localise an X linked RP
gene by establishing a linkage between an RP locus and the
marker L1.28 on chromosome X. As a result of extensive
studies undertaken by research teams throughout the world
we now know that two X linked RP genes exist on the short
arm of the X chromosome.2 However, at the time of writing
neither of these genes has been functionally characterised. A
great deal of progress has, however, been made over the past
five to six years into the aetiology of autosomal dominant
forms of RP (adRP). The first breakthrough came in 1989
with the establishment of an adRP locus on the long arm of
chromosome 3 as a result of a systematic linkage study in a
very -large pedigree of Irish origin.3 The gene encoding
rhodopsin, the light sensitive pigment of the rod photoreceptors, was found to map in very close proximity to the
disease locus.4 Shortly after these initial observations were
made a mutation within the rhodopsin gene (a pro-*his
substitution at codon 23) was identified by Dryja and
colleagues.5 This result prompted a massive search for further
mutations within the rhodopsin gene in cases of adRP. To
date approximately 60 different mutations have been
reported (reviewed by Farrar et a). The majority of these are
point substitutions although a number ofsmall deletions have
also been encountered.
Rhodopsin-based adRP, however, accounts for only about
20% of all dominant cases of the disease. Defects in other
genes must therefore be involved in the majority of other
families. Continued genetic linkage studies soon resulted in
the establishment of a second locus for adRP. This time a
gene was found on the short arm ofchromosome 6 close to the
locus for peripherin RDS.7 The RDS protein is a structural
component of the rod outer segment disc membranes and,
moreover, has been implicated in a retinopathy ofmice called
'retinal degeneration slow.'8 The linkage data indicated that
the RDS protein might also be involved in a retinopathy of
humans and soon several mutations within the RDS gene
were rapidly identified.9' These observations precipitated an
intensive search for further mutations within the RDS gene.
To data, approximately 20 mutations have been encountered
in various retinopathies.6 Most mutations are associated with
adRP. However a 2 base pair deletion has recently been
encountered in a case of RP punctata albescens" and, in
addition, a number of amino acid substitutions have been
encountered in various forms of hereditary macular degeneration. 12 13
Taken together, rhodopsin and RDS mutations probably
account for up to 30% of all dominant cases of RP and as yet
an undetermined proportion of cases of hereditary macular
dystrophies. Hence, the search for additional genes has
continued, and further linkage studies have resulted in the
establishment of other dominant RP loci at the centromeric
region of chromosome 8'4 and, more recently, on both the
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Humphries
470
short and long arms of chromosome 7."16 While these genes
remain to be isolated, additional pedigrees exist showing no
evidence for linkage at any of the five known loci. Thus, at
least six genes are implicated in the aetiology of various
autosomal dominant forms of RP or macular degeneration.
An exciting prospect will be the characterisation of such
genes over the next few years.
Progress in gene defect detection in autosomal recessive
RP, accounting for up to 50% of all cases, has been much
slower. However, it has recently been reported that a small
proportion of patients have defects in the gene encoding
cyclic GMP phosphodiesterase."7 Defects in this gene were
already known to cause the hereditary retinopathy of mice
termed retinal degeneration, or RD."Hunting for the genes
for recessive RP, however, using the technique of linkage
analysis is not so easy, primarily because fewer large families
suitable for linkage work are available. However, using a
combination oflinkage and candidate gene studies an increasing number of recessive retinopathy genes is likely to be
identified in the next few years.
What does all that tell us about the cause of RP in humans?
So far two proteins have been implicated in autosomal
dominant forms of the disease. The first is rhodopsin, the
primary component of the visual transduction cycle and the
second is peripherin RDS. The fact that defects in rhodopsin
have been identified in many cases of the disease renders
other components of the visual transduction cycle strong
contenders in disegse aetiology, and indeed defects in GMP
phosphodiesterase have now been implicated in a proportion
of recessive cases as outlined above. Other components of the
cycle, including transducin, guanylate cyclase the cGMPgated channel protein itself, arrestin, and rhodopsin kinase
must be strong contenders. In addition, because of the fact
that the RDS protein, a structural component of the photoreceptor outer segment disc membranes, has also been
implicated in some cases, this would imply that other
membrane proteins might also be involved. With regard to
how such proteins might exert their pathological effects,
Sung and others have recently obtained evidence that a
proportion of mutant proteins may not be effectively transported from the endoplasmic reticulum following synthesis.'9
Such defective transport could compromise the viability of
the rod photoreceptors. Alternatively, those mutant proteins
that do become incorporated into the outer segment disc
membranes may result in some form of structural destabilisation of the membranes themselves. A much more complete
picture will emerge following the isolation and characterisation of the additional genes which have recently been located.
Research in this field continues apace. In this issue of the
journal, Apfelstedt-Sylla et al describe yet another mutation
in rhodopsin, this time affecting the carboxyl terminal
sequence. In a second paper in this issue, Moore and
colleagues provide both clinical and molecular genetic data on
patients and families with forms of adRP which appear to
display incomplete penetrance. Lack of penetrance occurs
with varying frequencies in a variety of hereditary conditions.
It- is an intriguing phenomenon. An individual with early
onset dominant disease usually has a 50% probability of
passing the disease allele on to any of his or her children.
Occasionally however, non-affected individuals of affected
parents may themselves go on to have children who manifest
symptoms of the disease. Just why the non-affected individual escapes the development of disease symptoms when he or
she carries a dominant retinopathy gene is, at present,
unknown. However, the individual's own genetic background may well influence the activity or expression of the
RP-causing gene. Alternatively, environmental factors
(dietary intake or metabolism of vitamin A to give but one
possible example) could have a significant influence on the
expression, or otherwise, of mutated genes. Identification of
genetic and/or environmental components which might be
involved in the suppression of a disease phenotype is a major
and exciting challenge. The work reported in Moore et als
paper indicates that, in a number of families with adRP,
'asymptomatic' carriers of disease genes do in fact manifest
mild abnormalities on detailed ophthalmic examination.
Identification of the mutations involved in such families
(work in progress is reported) will represent an initial step
towards an understanding of a phenomenon which might
eventually provide major clues on modifying the phenotypic
effects of some disease-causing mutations.
PETER HUMPHRIES
University of Dublin,
Department of Genetics,
Lincoln Place Gate,
Trinity College,
Dublin 2
Bhattacharya SS, Wright AF, Clayton JF, Price WH, Phillips CI, McKeown
CME, etal. Close genetic linkage between X-linked retinitis pigmentosa and a
restriction fragment length polymorphism identified by recombinant DNA
probe L1.28. Nature 1984; 309: 253-6.
2 Ott J, Bhattacharya SS, Chen JV, Denton MJ, Donald J, Dubay C, et al.
Localization of multiple retinitis pigmentosa loci on the X-chromosome.
Proc NatlAcad Sci (USA) 1990; 87: 701-4.
3 McWiliam P, Farrar GJ, Kenna P, Bradley DG, Humphries MM, Sharp EM,
et al. Autosomal dominant retinitis pigmentosa (adRP): localization of an
adRP gene to the long arm of chromosome 3. Genomics 1986; 5: 619-22.
4 Farrar GJ, McWilhiam P, Bradley DG, Kenna P, Sharp EM, Humphries MM,
et al. Autosomal dominant retinitis pigmentosa: linkage to rhodopsin and
evidence for genetic heterogeneity. Genomics 1990; 8: 35-40.
5 Dryja TD, McGee TL, Reichel E, Hahn LB, Cowley GS, Yandell DN, et al. A
point mutation in the rhodopsin gene in one form of retinitis pigmentosa.
Nature 1990; 343: 364.
6 Farrar GJ, Jordan SA, Kumar-Singh R, Inglehearn CR, Gal A, Greggory C,
et al. Extensive genetic heterogeneity in autosomal dominant retinitis
pigmentosa. In: Hollyfield JG, Anderson RE, La Vail MM. Retinal
degenerations. 1993 (in press).
7 FarrarGJ,Jordan SA, KennaP, Humphries MM, Kumat-SinghR, McWilliam
P, et al. Autosomal dominant retinitis pigmentosa: localisation of a disease
gene (RP6) to the short arm of chromosome 6. Genomics 1991; 11: 870-4.
8 Van Nie R, Ivanyi D, Demant P. A new H-2 linked mutation, rdscausing retinal
degeneration in the mouse. Tissue Antigens 1978; 12: 106.
9 Farrar GJ, KennaP, Jordan SA, Kumar-Singh R, Humphries MM, Sharp EM,
et al. A 3 base-pair deletion in the peripherin gene in one form of retinitis
pigmentosa. Nature 1991; 354: 478-80.
10 Kajiwara K, Hahn LB, Mukai S, Travis GH, Berson EL, DryjaTP. Mutations
in the human retinal degeneration slow gene in autosomal dominant retinitis
pigmentosa. Nature 1991; 354: 480.
11 Kajiwara K, Sandberg MA, Berson EL, Dryja TP. A null mutation in the
human peripherin/RDS gene in a family with autosomal dominant retinitis
punctata albescens. Nature Genetics 1993; 3: 208-12.
12 Wells J, Wroblewski J, Keen J, Inglehearn C, Jubb C, Eckstein A, et al.
Mutations in the human retinal degeneration slow (RDS) gene can cause
either retinitis pigmentosa or retinal dystrophy. Nature Genetics 1993; 3:
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13 Nichols BE, Sheffield VC, Vandenburgh K, Drack AV, Kimura AE, Stone
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16 Inglehearn CF, Carter SA, Keen TJ, Lindsey J, Stephenson AM, Bashir R,
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17 Association for Research in Vision and Ophthalmology (ARVO) Abstracts.
May 1993.
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Retinal degeneration in the rd mouse is caused by a defect in the B subunit of
rod cGMP-phosphodiesterase. Nature 1990; 347: 677.
19 Sung CH, Schneider B, Agarwall N, Papermaster D, Nathans J. Functional
heterogeneity of mutant rhodopsins responsible for autosomal dominant
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Hereditary retinopathies: insights into a
complex genetic aetiology.
P Humphries
Br J Ophthalmol 1993 77: 469-470
doi: 10.1136/bjo.77.8.469
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