Mutations were sought in MECP2 in 48 females with classical sporadic RTT, seven families with possible familial RTT and five sporadic females with features suggestive, but not diagnostic of RTT.
The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.
Three of these mutations (R106W, R133C, and F155S) have their binding affinities for methylated DNA reduced more than 100-fold; this is consistent with the hypothesis that impaired selectivity for methylated DNA of mutant MeCP2 contributes to Rett syndrome.
The novel disease alleles and benign variants of the MECP2 gene found in this study should contribute to the establishment of a reliable diagnosis of Rett syndrome.
Although much is known about the biochemical function of MeCP2, the phenotype of Rett syndrome suggests that it plays an unexplored but critical role in development and maintenance of the nervous system.
Collectively, we tested 228 unrelated female patients with a diagnosis of possible (209) or classic (19) RTT and found MECP2 mutations in 83 (40%) of 209 and 16 (84%) of 19 of the patients, respectively.
Together, these results provide evidence of how Rett syndrome mutations can affect distinct functions of MeCP2 and give insight into these mutations that may contribute to the disease.
MECP2 encodes a methyl-CpG-binding protein (MeCP2), which is critical for transcriptional silencing of an as yet unknown number and type of genes responsible for the pathobiology of RS.
In order to provide further insights into the distribution and the spectrum of mutations, we investigated, in addition to the whole coding sequence, a phylogenetically conserved sequence within the 3' untranslated region (3' UTR) of the MECP2 gene for 55 sporadic RTT, including 47 typical and 8 nonclassical cases.
Mutations in the MECP2 (Methyl-CpG-binding protein) gene recently have been reported to cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disease.