Rett Syndrome Molecular Basis

Rett syndrome is an X-linked neurodevelopmental disorder that almost exclusively affects females. In the classic form of the disease, affected girls appear to develop normally until the age of 6 to 18 months followed by a characteristic pattern of regression, which includes deceleration of head growth leading to acquired microcephaly, autistic features, loss of speech and purposeful hand use, irregular breathing patterns, stereotypical hand wringing, and seizures.19 The frequency of classic Rett syndrome is approximately 1 in 15,000 females. Since the gene responsible for Rett syndrome was identified in 1999, however, a broader range of clinical phenotypes have been associated with mutation of this gene. The gene is MECP2 on chromosome Xq28, which encodes the methyl-CpG-binding protein 2.20 MECP2 binds preferentially to methylated DNA via its methyl-CpG-binding domain (MBD), and silences transcription by recruiting corepressor complexes through its transcriptional repression domain (TRD). Instead of serving as a global transcriptional repressor, as initially speculated, protein expression studies suggest that MECP2 may have a specialized role in neuronal maturation. The neuropathological findings in Rett syndrome of individuals with brains indicate that arrested neuronal development is an underlying feature of this disorder.21

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