Download The phenotypic consequences of MECP2 mutations extend beyond

MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES
RESEARCH REVIEWS 8: 94–98 (2002)
THE PHENOTYPIC CONSEQUENCES OF MECP2
MUTATIONS EXTEND BEYOND RETT SYNDROME
Sara Hammer1,4, Naghmeh Dorrani1,2, Joanna Dragich3, Shinichi Kudo5, and
Carolyn Schanen*1,2,3,4
1
Departments of Human Genetics, 2Pediatrics, 3Brain Research Institute, and the 4Mental Retardation Research Center,
University of California, Los Angeles, 695 Charles Young Drive South, Los Angeles, California
5
Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo, Japan
Although MECP2 was initially identified as the causative gene in
classic Rett syndrome (RTT), the gene has now been implicated in several
phenotypes that extend well beyond the clinically defined disorder. MECP2
mutations have been found in people with various disorders, including
neonatal onset encephalopathy, X-linked recessive mental retardation
(MRX), classic and atypical RTT, autism, and Angelman syndrome, as well as
mildly affected females and normal carrier females. To make matters more
complex, in approximately 20% of classic sporadic RTT cases and more than
50% of affected sister pairs, no mutation in MECP2 has been found. Xchromosome inactivation patterns can clearly affect the phenotypic expression in females, while the effect of the type and position of the mutation is
more apparent in the broader phenotype than in RTT. Both males and
females are at risk, although an excess of paternally derived mutations are
found in most cases of classic RTT. Thus, because of the range of disparate
phenotypes, the gene may account for a relatively large portion of mental
© 2002 Wiley-Liss, Inc.
retardation in the population.
MRDD Research Reviews 2002;8:94 –98.
Key Words: Rett syndrome; MECP2; Angelman; X-linked mental retardation
A
s a neurodevelopmental disorder that most commonly
strikes females, Rett syndrome (RTT) has been an enigmatic disorder since it was first recognized. The identification of mutation in MECP2 as the cause of most cases of
RTT affords us the opportunity to explore the mechanisms that
underlie the disorder both clinically and molecularly. However,
the gene involved is also proving to be a bit more complex in
terms of the heterogeneous manifestations of mutation. In examination of the broader phenotypes resulting from MECP2
mutations, the expressivity of the mutant allele in heterozygous
females with balanced X-inactivation patterns indicates that
some alleles show X-linked recessive effects, while the mutations found in RTT are dominant acting. These differentially
acting alleles also manifest as various phenotypes in males, as
males that are hemizygous for RTT causing MECP2 mutations
present with a severe neonatal encephalopathy, while males with
recessive-acting mutations exhibit nonspecific X-linked mental
retardation (MRX) phenotypes. In short, mutation in MECP2 is
not synonymous with RTT, and RTT is not always caused by
an identifiable mutation in MECP2. While this may seem like
semantics, it is important to distinguish the clinical diagnosis of
© 2002 Wiley-Liss, Inc.
RTT because there are data for complications and prognosis for
individuals with the more classical presentations that cannot be
applied across the broader phenotypes of those with MECP2
mutation. Finding connections between MECP2 mutation type,
penetrance, and phenotype in both males and females will
perhaps elucidate the mechanism by which mutation in MECP2
can cause several different forms of neurodevelopmental dysfunction.
SPECTRUM OF MECP2 MUTATIONS IN
CLASSICAL AND ATYPICAL RTT
In its classic form, RTT is generally a sporadic disorder
that is recognized in about 1/15,000 females. Although familial
cases of RTT occur, there are considerably more sporadic cases,
which reflects the relatively high frequency of mutation of the
human MECP2 gene. There is a propensity for C to T transitions, leading to nonsense and missense mutations, as well as
small deletions and insertions in the coding sequence (Fig. 1). In
classic cases, the rate of mutations identified approaches 80%–
90% [Amir et al., 2000; Cheadle et al., 2000; Hoffbuhr et al.,
2001], with lower rates in atypical cases (30%) [Hoffbuhr et al.,
2001]. In almost all of the familial cases used to map the locus,
mutations have been identified, however, only about 20 %–25%
of sister pairs have identifiable mutations [Amir et al., 2000]. In
karyotypically normal boys with RTT phenotypes, only a few
have had mutations in this gene, although it is responsible for a
plethora of other disorders in boys (see below). While it is
possible that patients with RTT who do not have mutations in
the coding regions of MECP2 have novel noncoding mutations
or large inversions or rearrangements that escape PCR-based
screening strategies, it seems likely that a second disease locus
exists that could contribute to some cases of RTT and atypical
Grant Sponsor: National Institutes of Health; Grant numbers: NIH T32 HD07032,
NIH MH19384, NIH RO1 HD37874
*Correspondence to: Carolyn Schanen, MD, PhD, Nemours Research Program,
Alfred I. duPont Hospital for Children, 1600 Rockland Road, PO Box 269, Room
H3B-337, Wilmington, DE 19899. E-mail: [email protected]
Received 11 October 2001; Accepted 6 November 2001
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/mrdd.10023
Fig. 1. The genomic organization of the MECP2 gene. It comprises of four exons (thick boxes),
and nucleotide positions relative to the ATG start codon are indicated. The thin, gray shaded boxes
indicate untranslated reg ions. Coding sequences for the methyl-binding domain (MBD) and
transcriptional repression domain (TRD) are indicated by [M] and [T], respectively, and the approximate positions of two nuclear localization sequences are shown by spiral markings. The long
3⬘-UTR contains two alternate polyadenylation signals, one at the end of the 3⬘ gray box, encoding
a short transcript (1.8kb), and one encoding a long transcript (⬇10kb). Missense (above) and
nonsense (below) mutations are denoted as follows: common RTT-causing mutations [F], MRXcausing mutations [], and mutations resulting in neonatal encephalopathy [■]. Stippled symbols
indicate somatic mosaicism.
Fig. 2. A representation of the overlap between RTT, atypical RTT, and MECP2 mutation, including the spectrum of broader phenotypes.
RTT. Whether this locus is X-linked is
unclear; however, the identification of
totally skewed XCI in some families with
recurrent RTT raises the possibility of a
second gene on Xp [Villard et al., 2000].
The dosage and mutation type of
MECP2 appear to contribute to disease
phenotype, although, within the domain
of classic and atypical RTT, specific genotype-phenotype correlations have had
mixed results. In part, this stems from
marked variability in the criteria used between groups to define clinical parameters, but also arises from variable expressivity of the same mutation in different
probands because of regional differences
in X-chromosome inactivation (XCI)
patterns. Within the classic and atypical
cases, nonsense truncating mutations
have been associated with awake respiratory dysfunction and nonrandom XCI,
while missense mutations have been
MRDD RESEARCH REVIEWS
●
linked with scoliosis [Amir et al., 2000].
Hoffbuhr et al. also reported that mutations lying in the N-terminus of MeCP2
correlated with a more severe phenotype
than mutations in the carboxy end of the
protein, measured by comparison of head
growth deceleration in patients with different MECP2 mutations [2001].
THE INFLUENCE OF XCI ON
MECP2 MUTATION
EXPRESSION
The MECP2 gene is subject to
XCI in females and, thus, the phenotypic expression of mutations is influenced by the relative activity of the normal and abnormal alleles in relevant tissues [Adler et al., 1995]. Although for
some X-linked genes, mutation leads to
secondary skewing of inactivation because of a selective advantage of cells
expressing the normal allele, this does not
PHENOTYPIC OUTCOME
OF
MECP2 MUTATIONS
●
appear to be the case for most mutant
forms of MECP2. Numerous studies of
XCI patterns in RTT indicate that most
probands have random inactivation patterns in blood, skin, and brain [Vorsanova et al., 1996; Webb and Watkiss,
1996; Zoghbi et al., 1990]. Nonetheless,
for girls with classic or atypical RTT
resulting from MECP2 mutation, it is
likely that the individual variability in
symptoms stems from regional differences in the XCI patterns in the nervous
system, although this is difficult—if not
impossible—to prove at this juncture.
Fortunate skewing of inactivation, defined as ⬎ 80% inactivation of the chromosome carrying the mutant gene, has
clearly been shown to have an ameliorating effect on the phenotype in several
normal or mildly affected carrier females
[Amir et al., 2000; Bienvenu et al., 2000;
Schanen et al., 1997]. Most importantly,
this includes mothers of seemingly sporadic cases of RTT. Although it is possible that the skewed inactivation results
from selection against the mutant allele,
in each of the known cases of asymptomatic carriers with fortunate XCI, an affected family member with the same mutation has a random pattern [Schanen et
al., 1997; Sirianni et al., 1998; Wan et al.,
1999]. Similarly, there is limited evidence suggesting that early truncating
mutations have deleterious effects at the
cellular level leading to secondary skewing of inactivation; however, these cases
were also ascertained because of the existence of a relative with RTT and balanced XCI. If there is no selection against
the mutant allele, presumably, unfortunate inactivation could also occur, but
may result in symptoms that are not recognized as being related to RTT (see
below).
Recent studies indicate that MECP2
mutations manifest in a broader clinical
presentation than those encompassed under the RTT spectrum (Fig. 2). Variability in expressivity of MECP2 mutations
in females is expected because of the influence of XCI; however, there are
growing data indicating that the effect of
mutation in males is equally complex.
The range of phenotypes in boys who are
hemizygous for MECP2 mutations extends from a neonatal onset-encephalopathy associated with early death to several
forms of non syndromic X-linked recessive mental retardation compatible with
long-term survival [Schanen et al., 1998;
Clayton-Smith et al., 2000; Meloni et al.,
2000; Orrico et al., 2000; Villard et al.,
2000; Couvert et al., 2001; Hoffbuhr et
al., 2001; Imessaoudene et al., 2001]. In
addition, RTT or RTT-like phenotypes
HAMMER
ET AL.
95
also occur in boys and may or may not
result from MECP2 mutation. The extreme variability in phenotype likely results in many males with MECP2 mutations being overlooked or diagnosed
with a neurodevelopmental disorder
more typically seen in males, such as
autism.
MALE PHENOTYPES
The first male phenotype clearly
linked genetically to RTT was identified
in boys born into kindreds with girls with
classic RTT. In these cases, the boys
were born with normal growth parameters following uneventful pregnancies
and deliveries. They then presented with
severe neurologic symptoms in the newborn period. Common symptoms included a static encephalopathy associated
with profound developmental delays, hypotonia, seizure, acquired microcephaly,
constipation, and respiratory irregularities
including central apnea [Schanen et al.,
1998; Villard et al., 2000; Hoffbuhr et al.,
2001; Ben Zeev et al., personal communication]. Blood and urine chemistries
were normal and cerebral imaging was
also normal [Schanen et al., 1998; Villard
et al., 2000] or showed signs of diffuse
atrophy [Ben Zeev et al., personal communication]. Additional features seen
have included recurrent urinary tract infections, ataxia, and repeated face
scratching movements that are reminiscent of the stereotypical hand gestures
often found in girls with RTT. In the
few cases recognized thus far, death occurred in the first few years of life and
resulted from respiratory complications.
Although these boys do not exhibit
symptoms that are defined to be part of
the diagnostic criteria for RTT, they
have been found to have MECP2 mutations implicated in classical RTT kindreds.
Mutation analyses of the MECP2
gene in these cases revealed nonsense
mutations in the TRD of MeCP2 in two
cases, R268fsX288 and G252fsX258, and
a common missense mutation in the
MBD, T158M (Fig . 1); these mutations
were also present in one or more family
members who presented with classical
RTT [Wan et al., 1999; Villard et al.,
2000; Ben Zeev et al., personal communication]. Hoffbuhr et al. reported two
additional cases that were identified because of similar symptoms occurring in
two brothers with no family member
with RTT [2001]. In these cases, the
mother carried an inversion involving
Xq28. Her sons had inherited the rearranged X-chromosome, which also carried a mutation in MECP2, a 32-base
96
pair frameshift deletion (1154(32del))
[Hoffbuhr et al., 2001]. Importantly,
most of these boys have been identified
because they were born into RTT kindreds, either inheriting their MECP2
mutation from an asymptomatic or
mildly affected carrier mother or via parental germline mosaicism. In case of
mildly affected or unaffected carrier
mothers, favorably skewed XCI patterns
prevented them from exhibiting more
than very mild symptoms [Schanen and
Francke, 1998; Wan et al., 1999; Villard
et al., 2000; Hoffbuhr et al., 2001]. The
frequency of sporadic cases of males with
RTT-causing mutations is impossible to
know because of the low likelihood of
ascertaining the cases due to the difficulty
in recognizing the relatively nonspecific,
albeit severe, features of this manifestation of hemizygosity for an MECP2 mutation.
A third neonatal encephalopathic
patient with a truncating mutation has
been identified who carries a P81fsX89
mutation, which causes a very early stop
in the MBD [Clayton-Smith et al.,
2000]. The mutation occurs before the
third splice site, so it is very likely that the
message undergoes nonsense mediated
decay (NMD) rather than translating into
a truncated protein. The patient’s phenotype is much less severe than those of the
late-truncating mutations; he had some
speech ability until the age of two, walks
with an ataxic gait, is hypotonic, began
experiencing seizures at age three, and
was still alive at the age of six [ClaytonSmith et al., 2000]. The patient is somatic
mosaic for this de novo P81fsX89 mutation, indicated by the presence of both a
normal and mutant band in restriction
digests of the MECP2 region [ClaytonSmith et al., 2000]. Somatic mosaicism is
most likely responsible for the milder
phenotype manifested by this male as
compared with those with the neonatal
encephalopathy phenotype. It is also possible that the absence of any MeCP2
protein is less detrimental than the presence of a truncated version that could
possibly have a dominant negative effect.
RETT SYNDROME IN
KLINEFELTER PATIENTS
Although the above patients with
neonatal onset encephalopathy have mutations in the gene responsible for many
cases of RTT, they do not meet the
defined diagnostic criteria for RTT.
However, there have been a few cases
reported in which Klinefelter syndrome
patients (karyotype 47, XXY) exhibit
hallmark symptoms of RTT, including
stereotypical hand movements, hypoto-
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PHENOTYPIC OUTCOME
nia, and a loss of acquired skills over an
extended period of time [Vorsanova et
al., 1996; Schwartzman et al., 1998; Leonard et al., 2001]. The presence of two
X- chromosomes in Klinefelter males
would lead to a similar situation as in
females with RTT who are mosaic for
expression of the mutant allele. RTT occurs in about 1/10,000 female births, and
the incidence of Klinefelter syndrome is
approximately 1/1,000 male births, so
Klinefelter and RTT are expected to coincide in only about 1/107 male births.
For this reason, very few cases of
Klinefelter patients with RTT have been
reported. Schwartzman, et al. reported a
sporadic case of RTT in a 47,XXY male
who presented with stereotypical hand
gestures, loss of purposeful hand movement and language skills, constipation,
ataxia, and apnea, all after an eightmonth period of normal development
[1998]. The additional X-chromosome
was found to be of paternal origin, and
the proband’s XCI pattern determined
to be random, although no MECP2
mutation was identified [Schwartzman
et al., 1998]. Leonard et al. [2001] reported a mosaic Klinefelter RTT male
(47,XXY[23]/46,XY[7] in peripheral
blood lymphocytes) with the T158M
mutation in MECP2. The proband exhibited hand wringing movements, hypotonia, constipation, myoclonic seizures
and gradual loss of speech and coordinated muscle movement. He is mentally
retarded and wheel chair bound [Leonard
et al., 2001]. Vorsanova et al. reported
another 47,XXY/46,XY RTT male
who was found to have an extra X- chromosome in 12% of his lymphocytes and
presented with a classical RTT phenotype [1996]. Although only a few cases
have been identified thus far, it is important to note that classical or atypical RTT
resulting from MECP2 mutation can occur in boys who carry an additional Xchromosome, either constitutionally or
in a mosaic form or who have a postzygotic mutational event leading to mosaicism of expression of the mutant allele.
There have also been a number of
boys reported who meet many or all of
the diagnostic criteria for RTT, but who
are karyotypically normal [Coleman,
1990; Philippart, 1990; Eeg-Olofsson,
1999; Jan et al., 1999]. Results of
MECP2 mutation analysis for most of
these cases are not known; however,
Hoffbuhr et al. screened nine boys in
their cohort and did not find MECP2
mutations in any of them [Hoffbuhr et
al., 2001]. In addition, one boy reported
by Leonard et al. meets all of the clinical
criteria for RTT but does not have a
OF
MECP2 MUTATIONS
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HAMMER
ET AL.
detectable MECP2 mutation [2001].
Thus, as is the case with some RTT girls,
there are boys who have clinical features
of RTT, but have no detectable mutation in MECP2.
MECP2 MUTATION AND MRX
IN MALES
The discovery of MECP2 not only
answered the long search for the faulty
gene in RTT, but also has shed new light
on the molecular defect underlying nonspecific MRX. The prevalence of MRX
is estimated as 1/600 to 1/300 in males
[Herbst and Miller, 1980; Glass, 1991]
and, therefore, it is considered a common
cause of mental deficiency in males. The
link between MECP2 and this heterogeneous group of disorders demonstrates
that hemizygosity of an MECP2 mutation is not always lethal in males and
could present as mental retardation or an
array of other neurological disorders
[Meloni et al., 2000; Orrico et al., 2000;
Couvert et al., 2001; Imessaoudene et al.,
2001].
Investigating the possibility of
MECP2 mutations in families and cohorts of males and females with X-linked
recessive mental retardation was triggered by the phenotypic variability of
these mutations in RTT. Meloni et al.
studied a three-generation family in
which the gene was mapped to Xq27.2qter, and candidate genes in the region
were excluded previously [2000]. They
identified a Q406X mutation in the uncle and nephew and their mothers. In
contrast to RTT, both males were macrocephalic and had normal growth, diarrhea, and retained purposeful hand skills.
They were severely mentally retarded
and never developed language. Facial hypotonia, sialorrhea, seizures, and ataxic
gate were all evident. One male exhibited spasticity in all limbs and a choreoathetotic movement in one hand while
the other had hypertonia only in the
lower limbs and bruxism. Despite a random X-inactivation pattern in blood leukocytes in both carrier females, one
showed borderline intelligence and mild
facial hypotonia while no physical and
mental abnormalities were observed in
the other [Claes et al., 1997].
In a second case of inherited
MECP2 mutation, Orrico et al. [2000]
identified a family in which four adult
brothers with severe mental retardation
were found to carry an A140 V mutation.
The maternally inherited mutation was
also passed on to the only daughter of the
family. The affected males presented as
normocephalic with impaired expressive
language, resting tremors, and slowness
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of movement. The females were shown
to have mild MR, microcephaly, poor
muscle build, and speech and gait difficulties [Orrico et al., 2000]. The A140V
and five other mutations, R167W,
E137G, P399L, R453Q, and K284E,
were detected in seven other cases of
isolated MRX where the common phenotypic presentation in the males was
moderate to severe MR [Couvert et al.,
2001]. In addition to MR, speech impairment, resting tremors, aggressive
behavior, and psychiatric disturbances including auditory and visual hallucinations, insomnia and anxiety were noted
in some of the patients. The probands’
mothers were carriers of the mutation
and had normal cognition and patterns of
X-inactivation [Couvert et al., 2001].
Imessaoudene et al. [2001] also reported
on the involvement of a G428S mutation
in the MECP2 gene and nonprogressive
encephalopathy in a male. Developmental delay, uncoordinated limb and trunk
movements, agitation, and absence of
language were the neurological disturbances reported. The mutation was
shared with the normal mother and two
maternal aunts who had balanced XCI
patterns. Importantly, the pathogenicity
of this mutation has not been established,
although it has not been reported in unrelated normal controls. In addition,
Imessaoudene et al. reported mutations
in MECP2 in patients who carried the
clinical diagnosis of possible Angelman
syndrome but had normal chromosome
15 methylation patterns [Imessaoudene et
al., 2001].
Although not lethal, similar to
RTT, MECP2 mutations in MRX seem
to affect primarily cognition and expressive language in the affected individuals.
It is interesting to note that regression
following a normal period of development, which is the hallmark characteristic
of classical RTT, has not been reported
in any of the cases. Surprisingly, XCI
studies in all females did not reveal any
abnormality; nonetheless, a non random
pattern of X-inactivation in tissues other
than blood is a plausible explanation for
the abnormal phenotypes observed.
THE MOLECULAR BASIS OF
VARIABLE EXPRESSIVITY OF
MECP2 MUTATIONS
The heterogeneity of phenotypes
caused by mutation in MECP2 is best
explained by the combined effect of XCI
and the likelihood that different mutations have variable impact on the function of MeCP2. Based on available data,
it appears that mutations that lead to classic RTT in females are most often asso-
PHENOTYPIC OUTCOME
OF
MECP2 MUTATIONS
●
ciated with the neonatal encephalopathy
phenotype in karyotypically normal
males [Wan et al., 1999; Villard et al.,
2000; Ben Zeev et al., personal communication]. These mutations are predicted
to have a more deleterious effect on
MeCP2 function than those found in
MRX. The T158M mutation involves
the substitution of a hydrophobic amino
acid with a polar residue in a hairpin loop
in the MBD of MeCP2. Although this
residue is on the opposite face of the
DNA binding domain, it is possible that
it is involved in interactions with other
portions of the MeCP2 molecule,
thereby stabilizing the protein structure
in relation to DNA [Free et al., 2001]. In
fact, it has been found that the T158M
mutation slightly reduces binding affinity
to methylated oligonucleotides and heterochromatin and has moderate effects
on transcriptional repression as well
[Ballestar et al., 2000; Free et al., 2001;
Kudo et al., in press]. Both the
R268fsX288 and G252fsX258 mutations
cause premature stops in translation in
the TRD, most likely forming a truncated MeCP2 protein. A truncated protein would disrupt the TRD but leave
the MBD intact, which could cause
MeCP2 to act in a dominant negative
manner by binding DNA but being unable to recruit the transcriptional repression complex. This could block methylCpG sites from being bound by other
functional methyl-CpG binding proteins.
Alternatively, binding of the MBD to
DNA could induce partial repression,
making these TRD stop mutations less
severe than missense mutations occurring
in the MBD. Loss of the carboxy-terminus of MeCP2 may also lead to protein
instability, potentially rendering the mutations as functionally null alleles. Understanding which of these molecular mechanisms actually occurs will perhaps
elucidate a connection between MECP2
mutation and the neonatal encephalopathy phenotype.
It is predicted that MRX-causing
MECP2 mutations have a less deleterious
effect on the MeCP2 protein than those
causing RTT, given the less severe phenotypes observed in both males and females [Orrico et al., 2000; Couvert et al.,
2001; Hoffbuhr et al., 2001]. The A140V
and E137G mutations both lie in the
␣-helix of the MBD. The wedge shaped
structure of the MBD is composed of
four antiparallel ␤-sheets, which form
one face of the wedge and are presumed
to interact with methylated CpG
dinucleotides in the major groove of
DNA [Wakefield et al., 1999]. Common
RTT causing mutations, such as R106W
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ET AL.
97
and R133C, lie in the region that forms
this face of the wedge. The ␣-helix that
harbors the A140V and E137G mutations
forms the opposite side of the wedge, and
is therefore not believed to directly interact with DNA [Ohki et al., 1999;
Wakefield et al., 1999]. The A140V mutation is predicted to shorten the length
of the ␣-helix by half, potentially having
a mild effect on MeCP2 function by
modifying the wedge shaped structure of
the MBD [Orrico et al., 2000]. In fact,
Kudo et al. demonstrated that the A140V
mutation does not alter MeCP2 affinity
for heterochromatin or transcriptional
repressive activity by a methylated promoter, but results in greater repression
from an unmethylated promoter [Kudo
et al., personal communication]. This
could result in nonspecific repression by
MeCP2 in the case of the A140V mutation, and therefore a phenotype different
from that of RTT. The less severe effects
of the P399L, R453Q, G428S, and
Q406X mutations are proposed to be
caused by their positions in the C terminus of MeCP2, a histidine and proline
rich region of the protein believed to
facilitate nonspecific binding to DNA
[Chandler et al., 1999; Couvert et al.,
2001; Imessaoudene et al., 2001; Meloni
et al., 2000]. The R167W mutation locates to the region between the MBD
and TRD, so a substitution here may not
perturb MeCP2 function as much as a
missense mutation lying directly inside
the MBD or TRD.
CONCLUSIONS
The diverse range of phenotypes
observed to be caused by mutation in
MECP2 not only sheds new light on the
possible consequences of MECP2 mutation at the molecular level, but has further ramifications in genetic counseling
as well. It is important to consider that
males can present with neurodevelopmental dysfunction as a result of MECP2
mutations, resulting in a neonatal encephalopathy phenotype, MRX phenotype or RTT-like phenotype, depending
on the mutation and whether they are
hemi- or heterozygous for the mutant
allele. It is suggested that about 2% of
MR cases are caused by a mutation in the
MECP2 gene [Couvert et al., 2001]. As
such, screening for MECP2 mutation in
nonspecific cases of MR needs to be considered and appropriate genetic counseling is warranted. The X-linked recessive
inheritance of MECP2 mutations and the
spectrum of phenotypes add to the complex task of elucidating the role of
98
MeCP2 in the nervous system. Why do
not MECP2 mutations in MRX demonstrate the same deleterious effect in males
as the ones in RTT? How do these mutations relate to the degree of perturbation of MeCP2 function? And how
could the spectrum of phenotypes in
males and females be explained? These
are a few questions that beg further exploration in light of these new findings.
f
ACKNOWLEDGEMENTS
We would like to thank David
Chiu for making Figure 1.
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