Download Molecular genetics of Rett syndrome and clinical

Molecular genetics of Rett syndrome and clinical spectrum of
MECP2 mutations
Mona D. Shahbaziana and Huda Y. Zoghbia,b,c
Rett syndrome, a neurodevelopmental disorder that is a leading
cause of mental retardation in females, is caused by mutations
in the X-linked gene encoding methyl-CpG-binding protein 2
(MeCP2). MECP2 mutations have subsequently been identified
in patients with a variety of clinical syndromes ranging from mild
learning disability in females to severe mental retardation,
seizures, ataxia, and sometimes neonatal encephalopathy in
males. In classic Rett syndrome, genotype-phenotype
correlation studies suggest that X chromosome inactivation
patterns have a more prominent effect on clinical severity than
the type of mutation. When the full range of phenotypes
associated with MECP2 mutations is considered, however, the
mutation type strongly affects disease severity. MeCP2 is a
transcriptional repressor that binds to methylated CpG
dinucleotides throughout the genome, and mutations in Rett
syndrome patients are thought to result in at least a partial loss
of function. Abnormal gene expression may thus underlie the
phenotype. Discovering which genes are misregulated in the
absence of functional MeCP2 is crucial for understanding the
pathogenesis of this disorder and related syndromes. Curr Opin
Neurol 14:171±176.
#
2001 Lippincott Williams & Wilkins.
Departments of aMolecular and Human Genetics and bPediatrics, and cHoward
Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA
Correspondence to Huda Y. Zoghbi, Departments of Molecular and Human Genetics
and Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030,
USA
Tel: +1 713 798 6523; fax: +1 713 798 8728; e-mail: [email protected]
Current Opinion in Neurology 2001, 14:171±176
Abbreviations
Dnmt1
DNA methyltransferase 1
GFAP
glial fibrillary acidic protein
HDAC1 and 2 histone deacetylases 1 and 2
ICF
immunodeficiency, centromere instability and facial anomalies
MBD
methyl-CpG-binding domain
MeCP2
methyl-CpG-binding protein 2
mRNA
messenger RNA
RLGS-M
restriction landmark genomic scanning using methylation-sensitive
endonuclease
RTT
Rett syndrome
TFIIB
Transcription Factor IIB
TRD
transcriptional repression domain
XCI
X chromosome inactivation
# 2001 Lippincott Williams & Wilkins
1350-7540
Introduction
Rett syndrome (RTT) was ®rst recognized as a distinct
clinical entity by Andreas Rett in 1966. It affects
approximately 1 : 15 000 females [1]. This review highlights the discoveries that have provided insight into the
cause of Rett syndrome, emphasizing the information
gained since the discovery of the causative gene.
Neurological deficits in Rett syndrome
Fifteen years after Hagberg described it as `a very
peculiar condition' [1], Rett syndrome continues to be a
subject of interest because of its unusual neurodevelopmental course and constellation of clinical features.
Classic Rett syndrome ®rst appears after six to eighteen
months of apparently normal development. Neurodevelopment is then interrupted, and affected girls begin to
regress intellectually. They lose acquired skills involving
language and purposeful hand use, and are generally
characterized as mentally retarded with autistic features
[2]. One particularly interesting symptom of RTT is the
replacement of hand skills with purposeless and stereotypic hand movements. Around the age of three years,
microcephaly becomes apparent, as a result of a
deceleration in head growth [2]. Gait ataxia and apraxia
are usually evident before the ®fth year [3] and other
features of Rett syndrome, such as apnea and hyperpnea,
seizures, scoliosis, and growth retardation, are common
[3].
Rett syndrome genetics
The early observation that Rett syndrome occurred
exclusively in females led to the hypothesis that it was
due to a dominant mutation on the X chromosome that
was lethal in hemizygous males [2]. Since affected
females rarely reproduce and familial cases are extremely
rare (less than one percent), it took years of research to
generate data supporting such a genetic mechanism. The
rarity of familial cases and the small size of the families
made conventional linkage analysis dif®cult, if not
impossible. An alternative strategy was to exclude
regions of the X chromosome by evaluating polymorphic
markers for concordance/discordance in affected individuals of familial RTT [4±7]. These efforts culminated in
the exclusion of most of the X chromosome, leaving
only Xq28 [8±10]. Although this substantially narrowed
the candidate region to about 10 megabases of DNA,
the causative gene remained elusive, since Xq28 is
171
172 Developmental disorders
extremely gene-dense. Given the list of neuronally expressed genes in the region, probably few would have
predicted that mutations would be found in the widelyexpressed gene encoding methyl-CpG-binding protein 2
(MeCP2) [11 .].
Biology of methyl-CpG-binding protein 2
The discovery of the causative gene for Rett
syndrome obviously answered an important question,
but it also opened up many more. Fortunately,
MeCP2 had already been identi®ed as a protein that,
through its methyl-CpG-binding domain (MBD),
bound to DNA oligonucleotides containing at least
one methylated CpG pair [12,13]. Consistent with this
®nding, the in-vivo distribution of MeCP2 paralleled
the broad distribution of 5-methyl-cytosine on the
chromosomes, encompassing pericentromeric heterochromatin and the euchromatic arms of mouse and rat
chromosomes [12].
Nan et al. [14] demonstrated that MeCP2 was suf®cient
to repress transcription from a promoter when the
upstream sequences were methylated. Upon the demonstration that the transcriptional repression domain
(TRD) of MeCP2 associated with the Sin3A corepressor
complex, which contains histone deacetylases 1 and 2
(HDAC1 and 2), the mechanism of repression was
clari®ed [15]. HDACs cause chromatin to condense by
removing acetyl groups from histones, and thereby make
the DNA inaccessible to the transcriptional machinery.
Recent evidence has demonstrated that the TRD also
interacts with Transcription Factor IIB (TFIIB), a
component of the basal transcriptional machinery,
suggesting an additional and direct effect in transcriptional interference [16].
The messenger RNA (mRNA) encoding MeCP2 is
present in a wide variety of tissues in humans and mouse
[17], but quantitative immunoblot analysis has shown
that levels are approximately six times higher in the
brain [12]. In situ studies of the developing and fully
differentiated mouse brain demonstrate expression
throughout the brain, with elevated levels in the
olfactory bulb and hippocampus [17].
Combining the functional data with expression studies,
it appears that MeCP2 binds to a multitude of
methylated chromosomal sites and modi®es chromatin
structure in a way that represses transcription. Additionally, the broad expression pattern of MeCP2
suggests that the protein is essential for chromatin
modi®cation/silencing in many tissues. These conclusions, however, are dif®cult to reconcile with the largely
neurological phenotype of Rett syndrome. The function
of MeCP2, therefore, is likely to be much more
complex.
Spectrum of MECP2 mutations and
connection to protein function
As a result of sequence analysis of DNA from Rett
syndrome cases, 78 unique MECP2 mutations have been
identi®ed in exons 3 and 4 of the gene, which contain a
majority of the coding region (Fig. 1) [11 .,18 .,19,20 .±
22 .,23,24 .,25 .,26,27]. MECP2 mutations have been
identi®ed in 75-90% of sporadic cases and approximately
50% of familial cases. Interestingly, C to T transitions at
eight different CpG dinucleotides in the gene account
for almost 70% of these mutations. The described
mutations suggest that RTT is due to a loss of protein
function. For example, one mutation (Q19X) introduces
an extremely early stop codon [25 .], which is likely to be
a null allele. Additional nonsense mutations have been
found in the MBD (Y141X), between the MBD and
TRD (R168X, Q170X, and R198X), and within
the TRD (R255X, K256X, R270X, and R294X)
[11 .,18 .,19,20 .±22 .,23,24 .,26,27]. Frameshift mutations
that give rise to premature stop codons also occur
throughout the gene. A partial loss of MeCP2 function
cannot be excluded, however, because premature stop
codons within the last exon may not lead to nonsensemediated mRNA decay [28]. Therefore, the possibility
still exists that premature stop codons within exon 4 may
produce a truncated form of the protein that retains
partial function. A truncated protein that retains the
MBD, for instance, may still be able to bind to methylCpG nucleotides and may, by virtue of solely binding
upstream of potential promoter regions, at least partially
interfere with transcription. Whether Rett syndrome is
caused by both null and hypomorphic alleles remains an
interesting question.
Missense mutations have been identi®ed in regions of
the gene encoding the MBD, TRD, and C-terminus of
the protein (Fig. 1). Three of the mutations within the
MBD (R106W, R133C, and F155S) have been shown to
reduce binding to methylated DNA by more than 100fold [29 .]. It remains to be shown whether missense
mutations in the TRD reduce interactions with the
Sin3A complex and whether mutations in the Cterminus, which enhances the binding of MeCP2 to
nucleosomal DNA [30], decrease interactions with
components of the nucleosome.
Phenotypic spectrum of MECP2 mutations
Since the MECP2 gene is X-linked and subject to X
chromosome inactivation (XCI) [31], one would expect
XCI patterns to have a potent in¯uence on phenotype.
Indeed, it has long been recognized that in addition to
classic Rett syndrome, there are milder forms of the
syndrome that lack certain signs [1], as well as very
severe forms that lack the period of normal development
and cause hypotonia and infantile spasms [32]. As more
mutation analysis is performed, the classi®cation of these
Rett syndrome and MECP2 mutations Shahbazian and Zoghbi 173
Figure 1. Summary of mutations found in the MECP2 gene
T158M
L124F
R106Q
R106W
P101H
P101L
P101R
P101T
D97E
D156E
F155I
F155S
P322A
P322L
R306C
R306H
P302A
P302H
P302L
P302R
P152R
A140V*
S134C
R133C
P225R
375delC
Q19X
378–2 splice
167–168delCC
407del507
258 –259delCA
+ins8
411delG
1036del154
1037del154
1038del154
1053ins10
+1141del55
1096del101
1098del70
+1182del7
1116del84
1130del69
1147del170
K256X
1152del41
1152del44
785del34
1157del41
803delG
1157del44
1158del10
807delC
1159del43
848del388
1163del26
849del388
1163del35
R294X
1165del26
1193insT
914del259
1194insT
Q406X*
R168X R198X
Q170X 602insG
620insT
654del4
677insA
Y141X
695delG
696delC
706delG
754del4
R255X
Coding
Untranslated
MBD
TRD
X487C
1364insC
Exons 2 through 4 of MECP2, containing the entire coding region, are illustrated. Missense mutations are shown above the genomic structure,
whereas nonsense and frameshift mutations are displayed below. Mutations include those found in Rett syndrome (unmarked) as well as nonsyndromic mental retardation (marked with asterisks).
different clinical entities as variants of one syndrome is
now being veri®ed at a genetic level [33]. In fact, it is
becoming evident that MECP2 mutations produce an
even wider range of phenotypes than previously
suspected (Table 1).
Two of the most interesting ®ndings about the
variability of clinical features resulting from MECP2
mutations have come from the analysis of familial cases
of RTT, four of which have been described. Four
members of one family bore the 803delG mutation: a
female with mild neurological and learning de®cits and
skewed XCI, her daughter and sister with RTT, and her
son with neonatal encephalopathy, who died at seventeen months [18 .]. In a second family, an asymptomatic
mother with completely skewed XCI, her daughter with
RTT, and her son with neonatal encephalopathy all
shared the T158M mutation [34]. Although DNA was
not available from another boy who died neonatally, the
R168X mutation was found in his three sisters with RTT
and in his normal mother with skewed XCI [18 .]. In a
fourth family, the R106W mutation was identi®ed in one
sister and a half-sister of a boy with neonatal encephalopathy, for whom DNA was not obtained, but not in their
normal mother, presumed to be germline mosaic [11 .].
Although the MECP2 mutation was con®rmed in only
two of the four male neonatal encephalopathy cases, it
appears that the same mutations that cause classic Rett
syndrome in females can also cause neonatal encephalopathy in males, whereas females can be spared part or all
of the neurological impairments through skewed XCI.
Although it is possible that cells expressing mutant
MeCP2 are selected against, this seems unlikely, since
the same mutation occurs in carrier females and in their
affected daughters. Therefore, the skewed XCI pattern
in carrier females is likely to be due to chance.
MECP2 mutations are not always lethal in males:
Clayton-Smith et al. [35] describe a boy with many
features of Rett syndrome, including loss of speech,
174 Developmental disorders
Table 1. Spectrum of phenotypes resulting from mutations in MECP2
Phenotype
Females:
Classic Rett syndrome
Mild forms of Rett syndrome
Preserved speech variant
Mild neurological and learning deficits
Mild mental retardation, microcephaly, speech
difficulties, gait abnormalities
None apparent
None apparent
Males:
Neonatal encephalopathy with respiratory dysfunction
Loss of speech, seizures, ataxia, scoliosis, decreased
head circumference, limited hand use
Severe mental retardation, impaired language
development, slow movements, resting tremors
Mental retardation, seizures, ataxia, absence of language
Mutations
Other genetic modifiers
Missense, Nonsense, Frameshift
Missense, Nonsense, Frameshift
Balanced X chromosome inactivation
Favorably skewed X chromosome inactivation
Missense
Balanced X chromosome inactivation
Missense, Nonsense, Frameshifta
Very late truncation
Favorably skewed X chromosome inactivation
Balanced X chromosome inactivation
Missense, Nonsense, Frameshiftb
Frameshift (early truncation)
Somatic mosaicism
Missense
Very late truncation
a
Mutations found in asymptomatic carrier females. bMutations demonstrated in two cases and presumed in two others based on mutations identified in
female siblings.
seizures, decreased head circumference, scoliosis, and
ataxia. Mutation analysis showed that this male probably
survived due to somatic mosaicism for a MECP2
mutation (167-168delCC), such that some of his cells
had the mutant allele and some had a wild-type allele,
much like females with random X chromosome inactivation.
Genotype-phenotype correlations in Rett
syndrome and related disorders
To determine whether different types of mutations in
MECP2 can account for the variability of phenotypes in
Rett syndrome, several groups have conducted genotypephenotype correlation studies. Amir et al. studied patients
with balanced XCI and classi®ed the genotypes as either
missense or truncation mutations; they found no correlation between genotype and overall clinical severity score
but did detect increased respiratory abnormalities and
decreased cerebrospinal ¯uid levels of homovanillic acid
in patients with truncations and increased incidence of
scoliosis in patients with missense mutations [20 .].
Neither Bienvenu et al. [21 .] nor Huppke et al. [24 .]
found any signi®cant correlation between mutation type
and clinical features. Nevertheless, Cheadle et al. found
that truncating mutations led to a more severe overall
phenotype than missense mutations, and that late
truncations correlated with a less severe outcome than
early truncations [22 .]. It thus appears that in classic Rett
syndrome, the correlation between mutation type and
phenotype is minimal, with XCI being a major determinant of clinical manifestations.
There appears to be a stronger correlation between
genotype and phenotype when neurological disorders
other than Rett syndrome are considered. Two groups
have screened cases of X-linked mental retardation for
mutations. Orrico et al. [36 .] found an A140V mutation in
four brothers with severe mental retardation and in their
mother and sister, who had mild mental retardation,
microcephaly, speech dif®culties, and gait abnormalities.
Since these males survived into adulthood and the
females had balanced XCI patterns [36 .], this mutation
may impair the function of MeCP2 less than those
causing Rett syndrome. In another study, Meloni et al.
[37 .] found that two mentally retarded males had a
Q406X mutation, which was also shared by two
unaffected carrier females ± who, unexpectedly, showed
balanced XCI patterns. The two males had delayed
development and macrocephaly, but, like Rett patients,
also displayed seizures, ataxia, and absence of language
[37 .]. Since the males survived into adulthood and the
females were normal despite balanced XCI, this mutation may be less deleterious to MeCP2 function than the
A140V mutation and much less than the mutations
causing Rett syndrome.
Pathogenesis of Rett syndrome
In view of the extensive binding pattern of MeCP2 on
chromosomes, how does one explain the neuronal
speci®city of Rett syndrome? One possibility might be
that the higher levels of MeCP2 detected in the brain
[12], particularly the hippocampus [17], signify areas
where MeCP2 function is uniquely essential. This
would imply that binding of MeCP2 to most methylated
chromosomal regions is dispensable since, if binding of
MeCP2 were indeed essential in every methylated
region, the consequence of its loss would be equivalent
to loss of methylation. Yet this is not the case: extensive
demethylation of the mouse genome by mutation of
DNA methyltransferase 1 (Dnmt1) is embryonic-lethal
[38], whereas mutation of the murine Mecp2 gene is not
[39]. Furthermore, mutations of another DNA methyltransferase, DNMT3B, in humans leads to a syndrome
characterized by immunode®ciency, centromere instabil-
Rett syndrome and MECP2 mutations Shahbazian and Zoghbi 175
ity and facial anomalies (ICF) [40,41]. In ICF syndrome,
genomic methylation is only partially lost, primarily in
satellites II and III of constitutive heterochromatin of
chromosomes 1, 9, and 16 [41]. Since the phenotype of
Rett syndrome does not include features of ICF, it
appears that MeCP2 is not essential for mediating the
effects of methylation of even this small subset of
methylated DNA. In addition, the fact that Dnmt3bde®cient mice, which have hypomethylated minor
satellite repeats in centromeric heterochromatin, also
die before birth [42] provides convincing evidence for
the dispensability of MeCP2 binding in these regions.
MeCP2 binding may be essential only for repressing
expression of a select group of genes, although the
mechanism that might account for this is dif®cult to
predict. These genes may be neuronal-speci®c or widely
expressed but detrimental only to neuronal development
when misexpressed. In support of the idea that MeCP2
might regulate only a subset of genes, the CpG islands
associated with the promoters of most genes are nonmethylated, and only a subset of genes are known to be
regulated by methylation (e.g., those that are either
imprinted or undergo inactivation on the X chromosome). There is a tight correlation in various cell types
between methylation and silencing as well as nonmethylation and expression for some genes that are
regulated in a tissue-speci®c manner, such as leukosialin
(CD43) [43]. Although the cause-and-effect relationship
is dif®cult to prove, it is certainly possible that
methylation patterns are responsible for the tissuespeci®c expression of some genes. For genes that may
be methylated in neurons and silenced by MeCP2, the
mutated protein could allow inappropriate expression
and thereby disrupt neuronal development.
It is worth noting that MeCP2 is a member of a growing
family of MBD-containing proteins [44]. Like MeCP2,
MBD1 has been shown to act as a transcriptional
repressor and to localize to centromeric heterochromatin
[45]. Another family member, MBD2, also represses
transcription in vitro and, along with MBD4, colocalizes
with regions of methylated satellite DNA [44,46]. With
the high level of functional similarity between these
proteins, it is possible that these or other comparable
proteins could substitute for at least the broad,
chromatin-binding role of MeCP2. Notably, no other
MBD-containing protein has been shown to have as high
af®nity for methyl-CpG dinucleotides as MeCP2, which
can bind just a single symmetrical pair [12]. Therefore,
MeCP2 may be the only family member that can silence
genes regulated by low methylation density, and it may
be misexpression of these genes that underlies the Rett
syndrome phenotype.
Another aspect of the Rett syndrome phenotype that is
dif®cult to reconcile with the expression pattern of
MeCP2 is the delay in the onset of overt features. One
possible explanation is that the genes repressed by
MeCP2 do not become methylated until later in
development. Several neuronal gene promoters have,
in fact, been found to undergo a developmental change
in methylation. With restriction landmark genomic
scanning using methylation-sensitive endonuclease
(RLGS-M), Suzuki et al. [47] showed that Stac, a gene
expressed primarily in brain (and at highest levels in the
hippocampus, cerebellum, and inferior olive), displays a
developmental change in methylation pattern in the
mouse brain. In addition, the glial ®brillary acidic protein
(GFAP) gene undergoes methylation during neuronal
maturation in the rat brain [48]. Furthermore, when
inducing differentiation with nerve growth factor, the
expression of genes encoding the helix-loop-helix
proteins Id1, Id2, and Id3 was reduced, but only in the
presence of DNA methyltransferase activity [49]. All
these examples demonstrate that neuronal maturation
may require changes in expression of genes mediated by
DNA methylation. Any of these genes, or other similarly
regulated genes, could be targets of MeCP2 repression.
Conclusion
The discoveries that the MECP2 gene was mutated in
Rett syndrome and in non-syndromic forms of mental
retardation provide a great advance in clinical neurology.
Patients with features resembling Rett syndrome, nonsyndromic mental retardation, and neonatal encephalopathy of unknown etiology can now be evaluated for
MECP2 mutations. Genetic counseling can be offered to
families with carrier females to reduce the risk of
recurrence. It remains to be determined why mutation
of the widely expressed MECP2 gene leads to a neuronal
phenotype, what genes are regulated by MeCP2, and
how mutations in MECP2 give rise to the characteristic
features of Rett syndrome. When suitable animal models
become available, addressing these perplexing issues
will be possible.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
.
of special interest
..
of outstanding interest
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