Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

Rett syndrome(1) (RTT, MIM 312750) is a progressive neurodevelopmental diso rder and one of the most common causes of mental retardation in females, wi th an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT a ppear to develop normally until 6-18 months of age, then gradually lose spe ech and purposeful hand use, and develop microcephaly, seizures, autism, at axia, intermittent hyperventilation and stereotypic hand movements(3). Afte r initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been p roposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males(3-8). Previous exclusion mapping studies using RTT fami lies mapped the locus to Xq28 (refs 6,7,9-11). Using a systematic gene scre ening approach, we have identified mutations in the gene (MECP2) encoding X -linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some Eases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacet ylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly co nserved methyl-binding domain (MBD) as well as a de novo frameshift and a d e novo nonsense mutation, both of which disrupt the transcription repressio n domain (TRD). In two affected half-sisters of a RTT family, we found segr egation of an additional missense mutation not detected in their obligate c arrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pa thogenesis of RTT.