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The Pathophysiology
of Fragile X Syndrome
Olga Penagarikano,1 Jennifer G. Mulle,1
and Stephen T. Warren1,2,3
1
Department of Human Genetics, 2 Department of Biochemistry and 3 Department of
Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322;
email: [email protected], [email protected],
[email protected]
Annu. Rev. Genomics Hum. Genet. 2007. 8:109–29
K ey Words
First published online as a Review in Advance on
May 3, 2007.
mental retardation, trinucleotide repeat expansion, FMR1, FMRP,
synaptic plasticity, autism
The Annual Review of Genomics and Human Genetics
is online at genom.annualreviews.org
This article’s doi:
10.1146/annurev.genom.8.080706.092249
Copyright c 2007 by Annual Reviews.
All rights reserved
1527-8204/07/0922-0109$20.00
A bstract
Fragile X syndrome is the most common form of inherited mental
retardation. The disorder is mainly caused by the expansion of the
trinucleotide sequence CGG located in the 5 UTR of the FMR1
gene on the X chromosome. The abnormal expansion of this triplet
leads to hypermethylation and consequent silencing of the FMR1
gene. Thus, the absence of the encoded protein (FMRP) is the basis
for the phenotype. FMRP is a selective RNA-binding protein that
associates with polyribosomes and acts as a negative regulator of
translation. FMRP appears to play an important role in synaptic
plasticity by regulating the synthesis of proteins encoded by certain
mRNAs localized in the dendrite. An advancing understanding of
the pathophysiology of this disorder has led to promising strategies
for pharmacologic interventions.
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IN TRODUC TIO N
F X : fragile X
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F ragile sites:
chromosomal
regions that appear
as nonrandom
chromatin
discontinuities at
metaphase during
cell division
F X S: fragile X
syndrome
In 1911, Thomas H. Morgan first pointed
out sex-linked inheritance of genetic traits in
Drosophila melanogaster when he noted that the
phenotype “white-eyed” affected only males.
Morgan suggested that there could be a recessive genetic trait affecting only males if the
gene responsible for it was located on the X
chromosome, in the region not common with
the Y chromosome. Twenty-five years after
Morgan described sex-linked inheritance in
flies, human studies were noting a higher incidence of mental retardation in males compared with females (90), and the first pedigrees
showing mental retardation associated to the
X chromosome were published (79). However, the idea of human intelligence being affected by X-linked genes was not fully appreciated until 1974, when Lehrke published
that 25–50% of mental retardation may be
attributed to X-chromosome mutations (73).
Although this estimation was later discovered
to be too high, his work established the concept of X-linked mental retardation (XLMR).
Today, approximately 2% of the general population has an intelligence quotient (IQ) below
what is considered normal (IQ < 70) and 15–
20% of this is believed to be due to XLMR,
with 202 conditions described, of which, to
date, 45 have the responsible gene cloned (22).
Although each of these X-linked MR loci contributes a relatively small percentage of human XLMR, one locus, that responsible for
fragile X syndrome, contributes the largest
fraction.
F R A G I L E X SY N D R O M E
One of the first large families where mental retardation was transmitted in an X-linked fashion was described by Martin & Bell in 1943
(79). In 1969, Lubs detected an unusual secondary constriction at the end of the long
arm of the X chromosome in four mentally
retarded males and three obligate carrier females in a single family (76) (F igure 1). However, this observation remained a mystery for
more than a decade until Sutherland showed
that specific culture conditions are needed for
the cytogenetic expression of the “marker X,”
enabling the recognition of additional families (105). Fragile sites are named with the
term FRA, designating fragility, followed by
the chromosome where they are located and a
letter indicating the order in which they were
found (14). Thus, the fragile site associated
to the fragile X chromosome, now localized
specifically to band Xq27.3 (53), was named
FRAXA, as it was the first fragile site described
on chromosome X. Richards & Sutherland
(93) later analyzed the original pedigree described by Martin and Bell and showed that
the affected males did indeed have fragile
X syndrome. Consequently, the descriptors
Martin-Bell syndrome or marker X syndrome
have now been largely superseded by the designation fragile X syndrome (FXS).
F RA G I L E X P H E N O T YP E
F igure 1
The “marker X” chromosome. Metaphase chromosomes showing the
peculiar constriction at the end of the long arm of chromosome X that is
characteristic in fragile X (FX) individuals.
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Initially, the fragile or marker X chromosome was not clearly associated with any other
phenotype but mental retardation. However,
once the laboratory conditions necessary for
the reproducible expression of the cytogenetic
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fragile site were established, a number of
affected families were detected and the associated phenotype emerged.
Mental retardation is the most prominent
phenotype, with IQ values typically between
20 and 70 (41). The cognitive dysfunction
particularly affects short-term memory for
complex information, visuospatial skills, and
speech. A delay in speech is common and often the first symptom that brings the child to
medical attention. Some patients show hyperactivity, hypersensitivity to sensorial stimuli,
and attention deficit, and between 15–50% of
affected individuals show some autistic behavior such as poor visual contact, tactile defensiveness, and repetitive behaviors (26).
Individuals affected by FXS show a subtle, yet characteristic, facial morphology
of macrocephaly, with a long narrow face
and prominent forehead, jaw, and ears (23)
(F igure 2). Macroorchidism, or enlarged testicles, are commonly seen in postpubescent
male patients. Other physical features such
as the presence of a high arched palate, hypotonia (51), flat feet, increased joint laxity,
and mitral valve prolapse (74) have also been
reported. These findings are collectively believed to be due to a poorly understood connective tissue abnormality that has received
little research attention (58).
Several investigators have also reported
a neuroendocrine dysfunction in FXS. Although poorly understood at the molecular
level, an unusual overgrowth pattern has been
attributed to this and includes an increased
birth weight, macrocephaly, and increased
stature, particularly in childhood. Some individuals affected by FXS have also been diagnosed as Sotos (115) or Prader-Willi syndromes (32) due to their striking physical
similarity. Endocrine studies of these patients
have reported hypothalamus dysfunction (55).
U N USU A L I N H E RI T A N C E
PA T T E R N
As soon as families showing the FX chromosome were identified, it became apparent
F igure 2
The fragile X phenotype. Note the characteristic
facial features of the syndrome: long, narrow face,
prominent forehead, jaw, and ears.
that the inheritance pattern was not consistent with a recessive X-linked condition, as
previously thought. The main conflicting data
were the existence of nonaffected male carriers and affected female carriers (84). Sherman
et al. (99, 100) conducted extensive pedigree
analyses and reported that 20% of males carrying the mutated gene were not affected.
These individuals were termed normal transmitting males (NTMs). In addition, 30% of
carrier females showed some form of mental
www.annualreviews.org • Fragile X Syndrome
M acroorchidism:
testicular volume
>30 ml, which is
principally
developed during the
postpubertal period
N T M : normal
transmitting male
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F M R1: fragile X
mental retardation 1
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M icrosatellite:
repetitive DNA
sequence consisting
of 1–4 base repeat
units
D ynamic m utation:
A repetitive DNA
sequence whose
increasing length,
beyond a certain
threshold, confers an
increasing
inter-generational
instability
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impairment. They also noticed that the risk
of inheriting the syndrome depended on the
position of an individual within the pedigree:
The mothers of NTM showed three times
less risk of having affected sons than their
daughters. This phenomenon is known as the
Sherman paradox and was not resolved until
1991, when the gene responsible for the syndrome was identified and, at the same time,
a new mutational mechanism revealing the
particular inheritance model: trinucleotide
repeat expansion.
A N E W C O N C EP T O F
M U TAT IO N
According to Mendel’s work in 1860, the
inheritance of genetic traits is determined
by units of discrete nature, later named
genes, which are transmitted intact and independently to the next generation. Almost
100 years later Benzer showed that genes
could suffer mutations, but, once produced,
these mutations would be transmitted intact to the next generation. This concept
is still valid for most genes; however, since
1991, when the gene responsible for FXS was
cloned, it has been revealed that specific repetitive sequences in some genes are unstable and
can mutate serially upon transmission.
T he F ragile X M utation
The existence of the Xq27.3 cytogenetic fragile site associated with the syndrome was
a target for subsequent molecular studies.
Pedigree analysis localized both the causal locus and the fragile site to a 22-cM region on
the X chromosome (88), and further studies
revealed a number of linked markers that reduced the interval to 1–2 Mb and strengthened the localization of the disease locus to
the fragile site (57, 95, 106, 107). Warren et al.
(117) described somatic cell hybrids carrying
the human fragile X chromosome with rodent chromosome translocations at the FX
site. Heitz et al. (54) identified a yeast artificial chromosome (YAC) containing two
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markers known to flank the fragile site hybrid break points and showed that this YAC
contains a CpG island aberrantly methylated
in fragile X patients. Furthermore, these abnormally methylated fragments were unstable
in affected individuals and increased in size
when transmitted through a pedigree (88).
In 1991, Verkerk et al. (114) used these somatic cell hybrids and identified a gene, expressed in the brain, that showed a tandem
repeat of the CGG trinucleotide in its 5 region, which was expanded in affected individuals and was coincident with the fragile site.
The gene was named Fragile X Mental Retardation 1 (FMR1), assuming that it was the first
of a number of yet-identified genes associated
with the FX site. We now appreciate that the
FMR1 gene resides in a gene desert, and this
single gene is responsible for the syndrome.
Microsatellite sequences, such as the one
responsible for FXS, are very frequent in the
human genome, being present every 2 kb
and representing approximately 90 Mb of the
human genome (62). Most of them show relatively high levels of polymorphism, but are
usually stable upon transmission. The variability in the repeat length represents a slight
instability in the sequence that usually appears
as an expansion or contraction of one or two
repeats (12). These small changes in repeat
length usually remain in the “normal” range;
therefore, most microsatellites are not associated with any disease. However, trinucleotide
repeats can show a much greater instability.
In particular, when the transmitting allele is
beyond a certain threshold size, it generates a
new lengthened allele when transmitted that
is often a large expansion that leads to genetic
disorders. This new and unexpected multistep
mutational mechanism is called dynamic mutation (94). FXS, along with Kennedy disease
[spinal-bulbar muscular atrophy (SBMA)],
was the first to be identified among the disorders associated with trinucleotide repeat expansion. To date, at least 16 disorders are
known to be caused by trinucleotide repeat expansion (28). The trinucleotide repeat
expansion can lie within the coding region
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of the gene, as in Kennedy disease or other
polyglutamine diseases, where the expanded
CAG triplet, which codes for glutamine, is
included in the encoded protein and the new
mutant protein gains a novel deleterious function. Alternatively, the triplet expansion can
be located in a noncoding region, as in FXS,
and, depending on the triplet and on the location (within an intron or within a nontranslated region of an exon), the pathogenic mechanism is different, usually leading to a diminished expression or even silencing of the gene.
occur; massive expansions could take place
by some continuous slippage due to a block
in the replication process generated by alternative structures formed by the trinucleotide
repeat sequences (89). Because slipped-strand
mispairing during DNA replication is the
most accepted mechanism of trinucleotide
repeat expansion, it is natural to think that
the mismatch repair system (MRS) would
play an important role. However, to date no
clear data exist regarding its role in triplet
repeat instability.
T rinucleotide R epeat E xpansion
T H E FMR1 G E N E
Since the molecular basis of this new mutational mechanism was described, special
efforts have been made to explain the
phenomenon of expansion. The proposed
models include unequal exchange of genetic
material during meiosis or mitosis due to
an incorrect pairing of the chromatids along
the repetitive sequence and gene conversion.
Although these mechanisms could be the
cause of some of the expansions observed in
trinucleotide repeats, the initial event leading
to the instability of a normal allele thought
to be slipped-strand mispairing during DNA
replication (70). Richards & Sutherland
(93) suggested that the slippage would occur
specifically in the Okazaki fragments. Okazaki
fragments formed by long or uninterrupted
repetitive sequences will not be anchored by
unique sequences at their ends, showing a risk
of suffering slippage. If slippage occurs, DNA
repairing enzymes could add nucleotides to
the template strand to make it complementary to the newly formed strand, generating
an expansion. In support of this, the absence
of a functional flap endonuclease 1 (FEN-1),
which is necessary for correct processing of
Okazaki fragments, has dramatic effects on
repeat instability. Indeed, FEN-1 activity is
diminished when the flap length is longer
than 11 repeats (72). If the flap is not correctly
processed, it will lead to an expansion of the
repeat. Initially, a gradual accumulation of
one or a few repeats per generation would
The FMR1 gene is 38 kb in length and contains 17 exons (F igure 3). The 4.4-kb fulllength mRNA codes for a protein with a
maximum length of 632 amino acids and a
molecular mass of 80 kDa, although different transcripts can be produced by alternative
splicing (7). The translation start is located
69 base pairs (bp) downstream the repetitive
region and the repeat lays in the 5 untranslated region (UTR) within the first exon of the
gene (7). In addition, the gene shows a CpG island located 250 bp upstream from the repeat
(38). The repeat length is polymorphic and
ranges from 6–54 CGG in normal individuals
(44). Female carriers and NTMs show an expansion between 55 and 200 repeats, termed
premutation. When the expansion is more
than 200 repeats, it is termed full mutation.
As a result of the expansion, the repeat, the
upstream CpG island, and the surrounding
sequence become hypermethylated and the
gene silenced. Thus, the absence of the encoded protein is the basis for the phenotype
(91). Silencing the expanded FMR1 allele is a
unique example of a local epigenetic change
driven by variation in the gene sequence.
Methylation of the FMR1 gene acts both
directly, by inhibiting the binding of transcription factors, and indirectly, by inducing chromatin condensation, which, in turn,
prevents the transcription machinery from
binding. The transcriptionally inactive status
of the FMR1 gene shows four occupied
www.annualreviews.org • Fragile X Syndrome
O kazaki fragment:
short fragment of
DNA created on the
lagging strand during
DNA replication due
to the intrinsic 5 –3
polarity of DNA
polymerase
F lap endonuclease
1 ( F E N -1): removes
5 flaps from Okazaki
fragments. Flaps
containing repeats
could acquire
different DNA
conformations that
enable them to
escape FEN-1
cleavage
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Transcription start
ATG
TAA
Introns
–129
–94
– 66
– 44
+1
Splicing
+130
GC rich
GC boxes E-box-CRE
palindrome
1
2 3 4 5
(CGG)n
Normal: 6-44
Intermediate: 45-54
Premutation: 55-200
Full mutation: >200
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Exons
6 7
NLS
8
9
KH1
10 11
KH2
1213 14
15 16
17
NES RGG
F igure 3
Schematic representation of the fragile X mental retardation 1 (FMR1) gene. The FMR1 gene shows 17
exons that undergo alternative splicing. The CGG repeat is located within the untranslated region of the
first exon. Expansion over 200 repeats leads to methylation of the promoter and transcriptional silencing.
The location of the principal domains of the normally encoded protein is also indicated.
transcription factor-binding sites in its promoter, including a palindrome, two GClike boxes, and an overlapping E-box-cAMP
response element (CRE) site. Studies on
the proteins that bind to these sites have
identified the factors upstream stimulatory
factor 1 (USF1) and USF2, nuclear respiratory factor 1 (NRF1) and NRF2, specificity
protein 1 (Sp1) and cAMP response element
binding protein (CREB) as the most actively
involved in FMR1 transcriptional activity (69,
103). In addition, the 5 region of the FMR1
gene is normally associated with histone proteins H3 and H4 acetylated in their lysine
residues, but this acetylation is reduced in
FX cells (25). Changes in histone methylation have also been described, with histone
3 showing methylated lysine 4 and unmethylated lysine 9 in normal cells but the opposite methylation pattern in FX cells (24).
Attempts to pharmacologically reactivate the
gene have shown a synergistic effect using
both DNA methylation and histone deacetylation inhibitors (20); however, the connection between histone modifications and DNA
methylation remains unclear. It was recently
shown that the transcriptionally active versus
inactive state of the FMR1 gene display different broader chromatin conformations. Chromatin segments located throughout a 50-kb
domain around the promoter interact less fre114
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quently when FMR1 is expressed compared
with when the gene is repressed. Therefore,
the expression-correlated change in conformation affects a significantly larger domain
than the one marked by histone modifications
(46). However, the cause-and-effect relationship among promoter activation, local histone
modifications, and broader changes in chromatin remains to be determined.
All data suggest that the transcriptional repression of the FMR1 gene occurs when both
the CpG island and the CGG repeat become
hypermethylated. It is assumed that methylation and consequent inactivation of the gene
occur after fertilization during embryogenesis and that the protein is expressed during
the first stages of embryonic development (75,
119). However, this early expression does not
seem to play an important biological role as individuals affected as consequence of deletions
in the FMR1 gene, and therefore not expressing the protein at any point during their development, do not show any phenotypic differences from individuals affected owing to gene
methylation (45, 120).
F actors I n fl uencing C G G R epeat
E xpansion
With FXS, as in every dynamic mutation,
there is a multistep process of expansion that
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takes place over many generations. Normal
repeats (6–54 CGG) are usually transmitted stably, but sometimes increase (or decrease) by a few repeats, creating a pool
of at-risk alleles that can eventually become
premutations. Premutations (55–200 CGG)
tend to expand when maternally transmitted,
as male spermatogenesis is unable to maintain full-mutation alleles (78). The probability of expansion depends on the repeat
length. Alleles larger than 90–100 CGG repeats show an almost 100% risk of expansion to full mutation (>200 CGG) in the
next generation (86). Smaller alleles, although
unstable, usually do not expand to a full
mutation in one generation. To date, the
smallest allele that has suffered that kind of
change has 59 repeats (87). In addition, sequencing analysis of normal FMR1 alleles revealed that the CGG repeat is not pure, but
presents an AGG interruption every 9–10 repeat units, and the most common allele is
(CGG)9 − 10 AGG(CGG)9 AGG(CGG)9 (71).
However, in FX families the premutated alleles usually have one or no interruptions.
Loss or lack of one of these interruptions
is an important determinant for repeat instability (37). The 59 repeat allele that expanded to a full mutation in one generation
had no interruptions, supporting their important role. The fact that most of the premutation alleles bigger than 90 repeats expand
to full mutation in one generation, and assuming that the maximum number of AGG
interruptions that they show is probably 2,
and that they are located every 9–10 CGG,
suggests that approximately 70 pure repeats
are needed for the allele to be fully expanded.
Because the most likely mechanism of expansion is slipped-strand mispairing during DNA
replication in the Okazaki fragments, which
range among 25–300 nucleotides, and 70 repeats make 210 nucleotides, there is a high
probability that this fragment is not anchored
by unique flanking sequences, which supports
the idea of strand slippage.
Analysis of polymorphic markers within
and near the FMR1 gene shows that certain
haplotypes are preferably associated with the
FX mutation. This observation is denoted as
linkage disequilibrium and suggests the existence of a pool of founder chromosomes
that lead to the FX chromosomes (71). Thus,
apparently nonrelated individuals could have
common ancestors, and the origin of the mutation could be the same. Different mutational
routes that correspond to the different haplotypes observed in FX individuals may exist.
They typically involve the generation of alleles with longer tracts of pure CGG repeats either by loss of AGG interruptions or by gradual increase in the repeat length.
It is still not clear when the repeat expansion occurs. First, the observation that affected individuals are mosaics, showing both
premutation and full-mutation alleles or fullmutation alleles of different sizes, together
with the fact that affected males show only
premutations in their sperm (42) led to the
assumption of a postzygotic model, where the
zygote harbors a premutation and the expansion occurs mitotically during early embriogenesis. It was later pointed out that there was
no correlation between the repeat length and
the degree of mosaicism and that no mechanism that distinguishes a maternal transmission, suffering expansion, from a paternal transmission, not suffering expansion, was
known. Therefore, the mosaicism observed in
patients would likely be due to the contraction
of somatic alleles rather than to the different expansion of maternal premutated alleles
during gametogenesis, and expansion would
probably be prezygotic (83). The prezygotic
model of expansion is supported by the observation of full-mutation alleles in oocytes and
in fetal spermatogonia, but only premutations
in testes at a later stage, suggesting that the
expansion must occur before germinal differentiation (78).
Animal models will be essential to determine the timing and the mechanism of both
the expansion and the methylation and inactivation seen in humans. However, although
some expansions were recently reported in a
mouse containing a human (CGG)98 repeat
www.annualreviews.org • Fragile X Syndrome
L in kage
disequilibriu m:
nonrandom
association of alleles
at two or more
linked loci
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P O F : premature
ovarian failure
F X T AS: fragile X
tremor ataxia
syndrome
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(15) (even occasionally reaching the fullmutation range), to date there are no reports
of massive expansions occurring in the mouse
at the same frequencies as are observed in human pedigrees. In addition, mice with long
repeats ( 230 CGG) show an absence of abnormal methylation, indicating that the FX
full mutation has not yet been mimicked in
mice.
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F ragile X Syndrome W ithout C G G
E xpansion
Because the cause of the phenotype associated
with FXS is the lack of the protein encoded by
the FMR1 gene, it is reasonable to think that
other mutations apart from the CGG expansion could lead to the disease. Actually, more
than 15 deletions affecting part of or the entire gene, and ranging from 1.6 kb to 13 Mb,
have been described (45, 52, 56, 63, 81, 109,
120). Besides deletions, point mutations that
lead to the phenotype due to the production
of a nonfunctional protein have also been described (31, 77). It is important to consider
that most diagnostic testing for FXS is limited to the examination of the CGG repeat
and largely ignores conventional mutations.
However, because the full mutation leads to
a functional null allele, it is likely that there
are many nonsense and missense mutations
of FMR1 that are being missed.
F RA G I L E X PR E M U T AT I O N
For many years, male and female premutation
carriers were considered asymptomatic. This
view was gradually challenged by reports of
different premutation-associated clinical phenotypes over the past decade. The prevalence of premutation alleles >54 repeats in
the general population is estimated at 1/259
females and 1/813 males (96). As early as 1986,
Fryns (43) noted an increased rate of twinning
among female premutation carriers, suggesting the possibility of ovarian dysfunction. A
few years later, Cronister et al. (27) noticed
that women carrying the FX mutation who
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were cognitively normal had a higher prevalence of premature ovarian failure. The mean
age of menopause in the general population is
51. It is assumed that it occurs as a result of
the reduction of the initial oocyte pool below
a determined level. Premature ovarian failure (POF) is defined as menopause before 40
years of age. Both genetic and environmental causes are known (97), but 60% of the
cases have no obvious cause. When premutation carriers could be distinguished from mutation carriers, it was shown that only the former showed this higher prevalence (16–24%),
whereas the latter showed the same risk as
noncarrier relatives and the general population ( 1%) (3). In addition, an increased level
of follicle-stimulating hormone (FSH), which
is as an indicator of ovarian aging, was found
in premutation carriers (104). Because only a
proportion of women who carry the premutation have ovarian dysfunction, it is important
to identify the risk factors that lead to clinical variability. The most obvious factors are
those related to the FMR1 gene. In a recent
report, Sullivan et al. (104) found a significant
influence of repeat size on the risk for ovarian
failure, with increasing prevalence of POF and
decreasing age at menopause correlating with
an increasing repeat size up to 100 repeats.
More recently, an emerging group of premutation carriers showing neurological problems was identified. Hagerman et al. (50) identified five male patients with clinical features
of intention tremor and cerebellar ataxia at
50–60 years of age. The disorder was designated as fragile X tremor ataxia syndrome
(FXTAS). Prior to onset, these patients had
normal cognitive ability. It was later shown
that this phenotype is not exclusive to males,
as earlier suggested, but that females can
also be affected, although they show a later
onset, likely due to the degree of inactivation of the affected X chromosome (49).
These patients show a general reduction in
brain size together with cerebellar damage,
severe loss of Purkinje cells, spongiosis of
the white matter, and axon dystrophy. In
addition, eosinophilic intranuclear inclusions,
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mainly formed by RNA and proteins, in neurons and astrocytes throughout the brain
were found in postmortem samples obtained
from symptomatic male premutation carriers (47). These types of granules have also
been found in other neurodegenerative diseases caused by trinuclotide repeat expansion,
such as polyglutamine diseases and myotonic
dystrophy.
The existence of phenotypes associated exclusively with the FX premutation suggests
that a molecular cause other than the reduction in FMRP levels must exist. mRNA levels
increased up to tenfold in premutation carriers, despite the reduction of FMRP expression (110). Transcriptional activity seems to
increase in response to a decreased translation
rate (40). A dominant RNA gain-of-function
mechanism has been proposed as the molecular mechanism underlying FXTAS. The elevated number of FMR1 transcripts present in
premutation carriers might result in sequestration of cellular proteins and formation of
inclusions. A mouse model for FXTAS that
displays similar neuronal intranuclear inclusions was recently generated (112). Further
research on the development and composition of the inclusions will help scientists to
better understand the mechanism of RNAmediated neurodegeneration. Ovarian dysfunction could also result from a toxic effect
on the follicles of an increased amount of
FMR1 RNA, leading to increased follicular
atresia rates rather than a reduction of the initial oocyte pool size. Future studies on ovarian
tissue from premutation carriers will be necessary to investigate this hypothesis.
F ragile X M ental R etardation P rotein
Understanding the pathogenesis of FXS involves studying its cause and, thus, the function of the molecule absent in affected individuals: FMRP. The protein encoded by
the FMR1 gene is expressed widely, particularly in the brain and testes (33), which
is consistent with the primary characteristics of the syndrome, mental retardation, and
macroorchidism. As a result of alternative
splicing, the FMR1 gene can generate at least
12 different proteins between 67–80 kDa (33,
101). Their expression does not seem to be tissue specific, as different tissues show the same
expression pattern (113). Alternative splicing
affects exons 12, 14, 15, and 17. In general,
the most common isoforms lack exon 12, and
isoforms lacking exon 14 show the lowest expression (102). FMRP is predominantly localized in the cytoplasm; however, it was shown
that isoforms lacking exon 14 were localized
to the nucleus, consistent with the identification of a nuclear exportation signal (NES)
encoded by this exon. FMRP also contains a
nuclear localization signal (NLS) in exons 1–
5, indicating that FMRP shuttles between the
nucleus and cytoplasm. This has been corroborated by electron microscopy (39).
FMRP shows sequence motifs characteristic of RNA-binding proteins. It has two
heterogeneus nuclear ribonucleoprotein K
Homology (KH) domains in exons 8 and 10,
an Arginine-Glycine-Glycine (RGG) box in
exon 15 (7), and an RNA-binding domain in
the amino-terminal region of the protein (2).
In vitro it binds to approximately 4% of the
mRNAs in fetal human brain, including its
own message (7). FMRP has also been shown
to associate with polyribosomes in an RNAdependent manner via messenger ribonucleoprotein particles (mRNP) of about 660 kDa,
which contain several other proteins including its two autosomal homologs fragile X related protein 1 (FXR1P) and FXR2P encoded
by autosomal genes localized to the chromosomal regions 3q28 and 17p13.1, respectively
(123). FXR1P and FXR2P show a 86% and
70% level of similarity with FMRP, respectively, and show the same principal functional
domains as FMRP: NLS and NES, the KH
domains, the RGG box, and a homodimerization domain. They are mainly localized
to the cytoplasm associated with polysomes
as part of the same protein complex. They
also shuttle between the nucleus and cytoplasm, and FXR2P shows a nucleolar localization signal (NoS) and shuttles between the
www.annualreviews.org • Fragile X Syndrome
F M R P: fragile X
mental retardation
protein
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Synaptic plasticity:
ability of the synapse
to change in strength
or change in
transmembrane
potential
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cytoplasm and the nucleolus (108). In addition to FMRP homologs, other proteins that
interact with FMRP or that are present in the
same complex have been identified. However,
it has not been determined whether all complexes are the same or if there are differences
in the associated proteins. If they were different, each complex could be affected by the
absence of FMRP in a different way. These
proteins include nuclear FMRP interacting
protein (NUFIP), cytoplasmic FMRP interacting protein 1 (CYFIP1) and CYFIP2, an
82-kD FMRP interacting protein (82-FIP),
nucleolin, and Y-Box factor 1/p50 (YB1/p50)
(10, 11, 17, 18, 98).
Posttranslational modifications of FMRP
have also been reported. FMRP was recently
shown to be normally methylated in the RGG
box, mainly in arginine 544, and this methylation seems to regulate its protein-protein and
protein-RNA interactions (35). FMRP also
shows a cluster of phosphorylated residues on
the N-terminal side. The primary site of phosphorylation is at serine 499 and it triggers
phosphorylation of nearby residues when the
residue is phosphorylated. This phosphorylation does not affect the rate of degradation
of FMRP or the species of RNA with which
FMRP is associated; rather, it has been observed that the phosphorylated form of FMRP
is associated with apparently stalled polyribosomes whereas the unphosphorylated form is
associated with actively translating polyribosomes, suggesting that phosphorylation could
regulate FMRP function (19).
Identification of FMRP mRNA ligands in
vivo will lead to essential information about
the functional roles of FMRP. Several works
have focused on the search for mRNAs bound
to the protein (16, 20, 29, 82). These experiments led to the identification of mRNAs
that encode for proteins with an important
role for neuronal function, synaptic plasticity, and neuronal maturation. Efforts are being made to elucidate the way that FMRP
regulates its target mRNAs. On one hand,
FMRP could recognize its targets directly.
Darnell et al. (29) showed that the RGG box
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binds to an RNA loop structure named G
quartet, where four guanines are stabilized
by Hoogsteen-type hydrogen bonds in a planar conformation. Most of the mRNA targets
identified for FMRP in the above-mentioned
studies contain a potential G-quartet structure (F igure 4). Chen et al. (20) identified another set of RNA ligands containing U-rich
sequences with 5–23 bases of repeating U
pentamers. In addition, the KH2 domain has
been shown to bind a complex RNA tertiary
structure named loop-loop pseudoknot or
“kissing complex” (30). The authors showed
that RNAs with this structure can compete
off the association of FMRP with polyribosomes, suggesting that this structure could
be crucial for FMRP translational regulation.
On the other hand, an indirect or more complex interaction between FMRP and its target mRNAs could occur. Recent data have
shown the association of FMRP with the
microRNA pathway, which suggests a new
way that FMRP could modulate translation.
MicroRNAs are short (21 nucleotides) noncoding regulatory RNAs that modulate gene
expression by blocking translation of partially
homolog mRNAs. MicroRNAs are processed
from longer RNAs by an RNAse III enzyme
named Dicer and are loaded into an RNAinduced silencing complex (RISC) protein
complex, which mediates the interaction between microRNAs and their mRNA targets.
FMRP associates with both microRNAs and
proteins from the RISC complex as well as
with Dicer activity, suggesting that it could
also be involved in processing microRNA
precursors (66). The “kissing complex” may
represent the interaction between an mRNA
and a microRNA or other noncoding RNA.
FMRP was reported to bind to the small
nonmessenger cytoplasmic RNA BC1, which
simultaneously associates to mRNA targets
known to be regulated by FMRP (122). BC1
has been suggested to mediate the formation of a translational inhibition complex
by association to a polyA-binding protein
and eIF4A (116). However, BC1 is found
in lighter polysome fractions than FMRP,
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46
a
47 G
48 G
GUC
AA
G
34
GG
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c
AGGGU
A
G
G 38
U
A
G
U
G 31
U
G
G
C
G
U
C
G
G
5'
AUGU
37
42
33
U
U
51 G
C
G
C
A
G
C
U
3'
G 43
40
b
U
U
U
U
GGCGGA U U
U
U
A G
U
UCCUA
UACA CUGCGUG
G
C
GG
U
U
G
A
A
UGGUC
3'
5' G G G
A
C
A
U
C
G
CCC
making their direct interaction unlikely (68).
Recent data support the interaction of FMRP
with the RISC complex in regulating synaptic protein synthesis. FMRP interacts with
the calcium-calmodulin-dependent kinase II
(CaMKII) mRNA, from which dendritic local protein synthesis is required for memory
formation (48). Translation of this mRNA is
inhibited by RISC and relieved by neuronal
stimulation, associating the miRNA pathway
with the control of local protein synthesis in
neurons (8).
A G A
A G A
ACCAGA
A U U C CG
U G A G GA
AU
CAG
A
G
G
F igure 4
RNA structures
recognized by fragile
X mental retardation
protein (FMRP).
(a) G quartet, (b) U
pentamer, (c) kissing
complex.
N E UR O N AL-M O L E C U LAR
CO N NEC TIO N
FMRP expression is widely seen during mouse
embryogenesis. During development, the expression level diminishes in some tissues,
leading to a more specific expression pattern (9). In humans, embryonic studies have
shown FMRP expression in the central nervous system of a 9-week-old fetus whereas
in a 25-week-old fetus FMRP expression
was restricted to neurons (1). Autopsies performed in individuals affected with FXS have
www.annualreviews.org • Fragile X Syndrome
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D endritic spine:
small membranous
extrusion that
protrudes from a
dendrite (branched
projections of a
neuron) and forms
one half of a synapse
Synapse: specialized
junction through
which cells of the
nervous system
signal to one another
from axons to
dendrites
L T P: long-term
potentiation
L T D : long-term
depression
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made the associated brain abnormalities apparent. They show more immature (longer
and thinner) dendritic spines, where most
of the synapses occur, and a higher density
of them, suggesting a possible misregulation
in their development and elimination (65).
An abnormal development of dendritic spines
in FMR1 knockout mice has also been reported (85). During development, synapses
are often produced in numbers that exceed
those that will ultimately survive. Maturation
and pruning are therefore important to establish the final synaptic pattern. Abnormalities in the dendritic spines have also been
associated with nonsyndromic mental retardation as well as with Down, Rett, CoffinLowry, and Rubinstein-Taybi syndromes (34).
One of the neurological problems in FXS
likely associated with this spine morphology is the presence of epileptic seizures because the characteristic spine morphology
could cause a greater neuronal excitation (64).
Specific proteins and biochemical pathways
have been associated with spine morphogenesis; many of these pathways ultimately
lead to actin rearrangement in the spine cytoskeleton. The local synthesis of FMRP can
potentially influence other proteins or signaling cascades involved in morphogenesis
such as Rac1, MAP1B, CaMKII, calbindin,
alpha-glucocorticoid receptor, and cadherins
(48). Thus, FXS is considered a synaptic
disease.
FMRP is an RNA-binding protein associated with polyribosomes, suggesting that
it has a role in modulating protein synthesis in neurons, where it is largely expressed.
In neurons, protein synthesis in both cell
bodies and dendritic spines is important for
synaptic plasticity, and certain mRNAs are
translated in response to a specific synaptic activation. Synaptic plasticity is essential for memory and learning processes and
involves long-term potentiation (LTP) and
long-term depression (LTD), which are associated with synapse creation and elimination in addition to synaptic transmission.
Depending on the brain region, synaptic plasPenagarikano
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ticity is expressed pre- and/or postsynaptically. At the postsynaptic level, LTD can
be triggered by the activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors or group I metabotropic glutamate receptors (mGluRs). Both types of LTD do
not occlude each other, but result in a decrease of surface expression of alpha-amino-3hydroxy-5-methylisoxazole-4-propionic acid
(AMPA) receptors (61). The activation of
group I mGluRs (mGluR1 and mGluR5) was
reported to stimulate the synthesis of FMRP
in synapses (118) and in neuronal lysate (59).
Fmr1 knockout mice (36) showed enhanced
mGluR-LTD in the hippocampal Schaffer
collateral synapses of the CA1 area (60) and
in the cerebellar parallel fiber to Purkinje cell
synapses (67). NMDAR-LTD in Fmr1 knockout mice remained the same as that in the
wild-type control, indicating that the phenotype was specific to the mGluR-dependent
form of synaptic plasticity. In addition, protein synthesis dependent on mGluR activation
was enhanced in the absence of FMRP (60).
These data led to the hypothesis that FMRP
normally represses further protein synthesis
(13). It was recently shown that the rapid
increase in FMRP synthesis associated with
the stimulation that can cause mGluR-LTD
is transient and followed by a rapid decrease
in FMRP back to baseline levels, suggesting
that FMRP is dynamically regulated during
mGluR-LTD, with rapid synthesis followed
by rapid degradation in hippocampal slices
and homogenate. The authors also showed
that the ubiquitin-proteasome degradation
pathway played a role in FMRP regulation
after mGluR stimulation because FMRP was
polyubiquitinated in the same temporal window where its levels begin to decline (59).
Therefore, it is reasonable to propose that
the rapid degradation of FMRP might be required to permit its target mRNAs to be translated and consolidate mGluR-LTD. In addition to local protein synthesis at synapses,
FMRP appears to be involved in the mRNA
transport to the synaptic locations. Stimulation of mGluRs increases the transport of
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FMRP-containing granules to the dendrites
(5, 6). Together, these data suggest a dual role
for FMRP: delivery and release of mRNAs for
activity-dependent translation.
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T REAT M E N T
Useful guidelines for health supervision of
FX children were published by the American
Academy of Pediatrics (4) and include advice
for both physical and behavioral components
of the syndrome. The therapy currently used
in FX individuals is designed specifically for
each patient and is focused on his/her specific
behavior symptoms. Unfortunately, there is
not yet a treatment to compensate for the absence of FMRP. Attempts have been made to
reactivate the silenced FMR1 gene and therefore restore the production of the protein (21,
92); however, reactivation processes are too
general and genes other than FMR1 may be
reactivated. In addition, toxicity of such approaches is very high. Regardless, reactivation
of a full mutation would still produce a transcript with a long repeat that renders the message inefficiently translated. The possibility
of gene therapy is currently not possible due
to difficulties in the delivery of the normal
gene into neurons and its restoration of the
phenotype.
More recently, the understanding of the
function of FMRP and the consequence of
its absence has led to potential therapeutic approaches. Because FMRP is a translational suppressor and mGluR 5 activation of
the excitatory pathway stimulates local protein synthesis, the absence of FMRP leads
to the apparent overstimulation of translation
by mGluR5 signaling (13). This imbalance,
which has fundamental consequences with regard to synaptic plasticity, may be countered
by mGluR5 antagonists (F igure 5). One such
antagonist is MPEP. Remarkably, MPEP was
recently shown to be highly efficient in rescuing phenotypes associated with FMRP loss
in animal models for FXS. In the Drosophila
model, McBride et al. (80) showed that MPEP
can rescue memory deficits in courtship be-
mGluR1/5
mGluR1/5
Drug
targets?
Translation stimulation
mRNA
translation
FMRP
Normal
mRNA
translation
Translation suppression
FMRP
Fragile X
syndrome
F igure 5
Role of fragile X mental retardation protein (FMRP) in modulating
synaptic plasticity. The activation of group I metabotropic receptors
(mGluR) stimulates translation of specific mRNAs at synapses. FMRP
normally acts as a translational repressor regulating such expression;
however, in the absence of FMRP, overexpression of such messages is
found.
havior and mushroom body defects observed
in mutant flies. Similarly, Yan et al. (121)
showed that FMR1 knockout mice treated
with MPEP exhibit a reduction in the sensitivity to audiogenic seizures and respond better to the open field test, with a reduced tendency to mainly be in the center of the field.
Using zebrafish as a model for the study of
human FXS, Tucker et al. (111) recently reported that MPEP was able to rescue the axonal branching defect observed in these animals. These data indicate that the interaction
between mGluR signaling and FMR1 function is responsible for some of the symptoms
associated with FXS. Thus, drugs targeting
mGLuR5 or downstream signaling may be of
therapeutic potential in FXS. It is anticipated
that clinical trials will begin within the next
two years. FXS is instructive regarding genetic
disease in general. Once given the “toe hold”
of the identification of the responsible gene,
basic scientific investigation into the normal and abnormal function of encoded proteins can lead to sufficient molecular understanding to suggest traditional pharmacologic
interventions for even the most seemingly
intractable disorders.
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S U M M A RY P O I N T S
1. FXS is the most common form of inherited mental retardation, has striking behavioral
overlap with autism, and may be considered the best-understood form of autism.
2. FXS is caused by the functional absence of FMRP encoded by the FMR1 X-linked
gene, usually due to silencing of the gene caused by expansion of the trinucleotide
repeat CGG located in its 5 UTR.
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3. FMRP is a selective RNA-binding protein associated with polyribosomes and expressed in neurons including the dendritic spine, where it has been shown to regulate
translation of mRNAs important for synaptic plasticity and neuronal maturation.
4. How FMRP plays its role in translational regulation is still unclear and involves direct
interaction with mRNAs as well as interaction with the microRNA pathway.
F U T U R E ISS U E S T O B E R E S O L V E D
1. Animal models for both expansion of the CGG repeat and silencing of the FMR1
gene will be essential to determine the timing and mechanism of repeat expansion
and subsequent epigenetic changes in FMR1.
2. The molecular details of how FMRP regulates mRNA translation need to be elucidated as does the regulation of FMRP itself.
3. A better understanding is needed of the role of FMRP in local protein synthesis in
the dendrite, its normal role in synaptic plasticity, and the neuronal consequence of
its absence.
4. Pharmacological approaches have been identified that may compensate for the loss of
FMRP, and therapeutic approaches now need to be developed to improve the quality
of life of patients with fragile X syndrome.
D IS C L O S U R E S T A T E M E N T
SW serves as Chair of the Scientific Advisory Committee for Seaside Therapeutics, Inc.
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7. K ey report
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R N A -binding
properties of
F M R P and giving
the fi rst insight
into its molecular
function.
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in synaptic
plasticity where the
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psychiatric aspects
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H u man G enetics
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C ontents
Volume 8, 2007
H uman E volution and Its Relevance for G enetic E pidemiology
Luigi Luca Cavalli-Sforza ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 1
G ene D uplication: A D rive for Phenotypic D iversity and C ause of
H uman D isease
Bernard Conrad and Stylianos E. Antonarakis ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 17
D N A Strand Break Repair and H uman G enetic D isease
Peter J. McKinnon and Keith W. Caldecott ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 37
T he G enetic L exicon of D yslexia
Silvia Paracchini, Thomas Scerri, and Anthony P. Monaco ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 57
Applications of R N A Interference in M ammalian Systems
Scott E. M artin and N atasha J. Caplen ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 81
T he Pathophysiology of F ragile X Syndrome
Olga Penagarikano, Jennifer G. Mulle, and Stephen T. Warren ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 109
M apping, F ine M apping, and M olecular D issection of Q uantitative
Trait L oci in D omestic Animals
M ichel Georges ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 131
H ost G enetics of M ycobacterial D iseases in M ice and M en:
F orward G enetic Studies of B C G -osis and Tuberculosis
A. Fortin, L. Abel, J.L. Casanova, and P. G ros ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 163
C omputation and Analysis of G enomic M ulti-Sequence Alignments
M athieu Blanchette ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 193
microR N As in Vertebrate Physiology and H uman D isease
Tsung-Cheng Chang and Joshua T. Mendell ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 215
Repetitive Sequences in C omplex G enomes: Structure and E volution
Jerzy Jurka, Vladimir V. Kapitonov, Oleksiy Kohany, and M ichael V. Jurka ! ! ! ! ! ! ! ! 241
C ongenital D isorders of G lycosylation: A Rapidly Expanding D isease F amily
Jaak Jaeken and Gert M atthijs ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 261
v
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Annotating N oncoding R N A G enes
Sam G riffiths-Jones ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 279
U sing G enomics to Study H ow C hromatin Influences G ene Expression
Douglas R. H iggs, Douglas Vernimmen, Jim Hughes, and Richard Gibbons ! ! ! ! ! ! ! ! ! 299
M ultistage Sampling for G enetic Studies
Robert C. Elston, D anyu Lin, and Gang Zheng ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 327
Annu. Rev. Genom. Human Genet. 2007.8:109-129. Downloaded from arjournals.annualreviews.org
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T he U neasy E thical and L egal U nderpinnings of L arge-Scale
G enomic Biobanks
H enry T. G reely ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 343
I ndexes
C umulative Index of C ontributing Authors, Volumes 1–8 ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 365
C umulative Index of C hapter T itles, Volumes 1–8 ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! 368
E rrata
An online log of corrections to Annual Review of Genomics and Human Genetics
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Contents