THE SILENCE IN RETT SYNDROME
number of genetic disorders seem to attract more than their fair
share of attention from human and medical geneticists. Some diseases
(such as cystic fibrosis) achieve this status because they are quite
common and exact a substantial toll on both patients and the medical
community. Others (such as fragile-X syndrome) do so because they
present with unusual genetic or clinical features that defy conventional
explanations. Discovery of the genetic and molecular basis of such
disorders, therefore, promises to reveal new concepts or mechanisms
of genetic disease, the significance and general interest of which
extend far beyond the details of the particular disorder itself.
such disorder is Rett syndrome (RTT), a childhood neuro-developmental
disorder that affects females (almost exclusively). Its genetic
basis has been difficult to establish, because most cases are sporadic.
Moreover, affected girls are considered to have normal development
for the first 6 to 18 months, followed by a period of regression
(sometimes abrupt), marked in particular by loss of purposeful hand
use and speech. Hand-wringing, ataxia and growth retardation often
accompany a profound mental handicap.
marks the Spot?
number of models that account for the genetics of RTT have been
proposed. The simplest explanation is that RTT is an X-linked dominant
condition, lethal in hemizygous males. The absence, however, of
a convincing deficit of males contrasts with other X-linked disorders
of this type. A high proportion of de novo mutations (particularly
in the paternal germ line) might account for the absence of obvious
male lethality, but the incidence of RTT (an estimated 1 in 10,000)
would require a very high mutation rate. The recognition of an X-linked
dominant disorder with male sparing provides another model. Because
of the sex-limited expression of RTT, most attempts to identify
the causative gene have centered on the X chromosome. Tantalizing,
but inconsistent, hints of skewed X-chromosome inactivation in females
with RTT or their mothers also implicate the X. Whereas attempts
to map the gene have been hindered by the frustratingly small number
of familial RTT cases available, exclusion mapping based on comparison
of X-chromosome haplotypes among affected sisters or half-sisters
has focused attention on Xq28.
Amir and colleagues now report the fruits of their labours over
Xq28: the presence of several mutations in MECP2 in a proportion
of RTT patients. The methyl CpG-binding protein 2 (MeCP2) can bind
methylated DNA and has been implicated as a key player in assembling
transcriptional silencing complexes. These data provide a link between
the genetics of RTT and epigenetic silencing and establish RTT as
the first human disease caused by defects in a protein involved
in DNA methylation. Notably, they add RTT to the small, but growing,
number of human genetic disorders that involve abnormal chromatin
packaging and gene expression.
relationship between chromatin structure, gene expression and DNA
methylation has long been recognized, but the role of methylation
in vertebrate development is poorly defined. Indeed, the only genes
whose appropriate expression patterns are known to depend on methylation
are those whose CpG islands need to become methylated for epigenetic
MeCP2 protein silences methylated chromatin by recruiting a histone
deacetylase complex. Unlike most other known transcriptional repressor
proteins, however, the binding site of MeCP2 occurs frequently in
vertebrate genomic DNA, as it requires only a single methylated
CpG base pair to bind. What might be the role of such a ubiquitous
transcriptional repressor? It has been proposed that MeCP2 acts
as a global transcriptional repressor that prevents unscheduled
transcription throughout the genome. Could the pathology of RTT
patients be caused by excessive transcriptional ‘noise’ owing to
a silencing defect? The fact that RTT patients do not suffer severe
abnormalities during early development implies that no specific
programmes of developmental gene expression (including X-chromosome
inactivation) are disrupted in the absence of MeCP2. But if genomic
noise is to blame, why is the brain the primary site of pathology?
MeCP2 is more abundant in the brain than in any other tissue, so
perhaps the brain is more sensitive to excess transcriptional noise
than are other tissues. Alternatively, perhaps more MeCP2 is needed
to keep noise to an acceptable level in the brain than in other
tissues. But although a defect in gene silencing is a logical and
exciting possibility in RTT, it remains unproven. Genes that are
targets of MeCP2 (whether specific or more global) need to be identified
and their possible over- or mis-expression in RTT, particularly
in the nervous system, evaluated.
finding that MECP2 is mutated in RTT fits well with what is known
about MeCP2 deficiency in mice. Male mouse embryonic stem (ES) cells
in which Mecp2 is disrupted cannot support development, consistent
with the possible male lethality of RTT. In contrast, chimaeric
mice, in which a small proportion of cells are derived from MeCP2-deficient
ES cells, are viable. These animals might provide a model for RTT,
as female RTT patients are also mosaic for MeCP2-expressing and
MeCP2-deficient cells because of random X-chromosome inactivation.
Conditional mouse mutants, in which Mecp2 is specifically disrupted
in the brain, may provide further clues as to the reasons for the
specific neurodevelopmental effects of MeCP2 deficiency.
is but one of three proteins known to both bind specifically to
methylated DNA in vivo and to be capable of repressing transcription.
Might other methyl-binding family members also factor in RTT, given
that MECP2 mutations have been found in a proportion of patients?
As the genes for other methyl-binding proteins are autosomal, mutation
of them is unlikely to cause RTT, unless there are autosomal phenocopies.
Nonetheless, the discovery that mutations in a gene that affects
DNA methylation lead to human disease implicates the autosomal genes
as candidates for other neurological disorders.
of MECP2 mutations by Amir et al. Identifies RTT as one of a small
but growing number of human diseases involving abnormal chromatin
assembly or remodelling, with consequent epigenetic effects on expression
of one or more genes that are themselves not mutated. Other examples
include patients with imprinting defects who demonstrate inappropriate
gene expression due to alterations in epigenetic regulation. Similarly,
patients with abnormal X chromosomes that are missing the X-inactivation
centre fail to inactivate that X and therefore have functional disomy
of X-linked genes. Recently, Allis and colleagues discovered a defect
in phosphorylation of histone H3 in Coffin-Lowry syndrome, suggesting
that its pathogenesis may be effected by global abnormalities in
gene expression. So, these examples focus renewed attention on chromatin
as a critical, but often overlooked, component in the cascade of
regulatory mechanisms that not only underlie gene activation or
silencing, but are also relevant to human disease.
Department of Genetics
Center for Human Genetics
Case Western Reserve University
University Hospital of Cleveland
Cleveland, Ohion 44106
Brian D. Hendrich
Institute of Cell and Molecular Biology
University of Edinburgh
Edinburgh EH9 3JR, UK
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