Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome.

Rett syndrome is an X-linked dominant neurodevelopmental disorder primarily affecting girls. About 80% of classic Rett syndrome is caused by mutations in the gene for methyl-CpG-binding protein (MeCP2) in Xq28. MeCP2 links DNA methylation to transcriptional repression, and MECP2 mutations likely cause partial or complete loss of function of the protein, leading to inappropriate transcription of downstream genes at critical times in brain development. More severe and milder variant forms can all be caused by similar mutations. Most classic Rett syndrome patients have random X-chromosome inactivation (XCI), but skewed patterns are present in a few. All asymptomatic or mildly mentally delayed female carriers studied to date have non-random XCI patterns, suggesting that this attenuates the deleterious effects of the MECP2 mutations in these women. The finding of non-random XCI patterns in some patients with very early truncations is consistent with this observation and supports that many mutations could cause partial and not complete loss of function. Our observation that the mutant mRNA is stable in three patients with truncating mutations supports this possibility. Further studies will have to be performed to better understand the functional consequences of MECP2 mutations in RTT.