Rett syndrome1 (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000–15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6–18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements3. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males3,4,5,6,7,8. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase 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 conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier 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 pathogenesis of RTT.
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We thank the Rett families for their participation and for motivating us as we sought the cause of this disease; the Blue Bird Circle Rett Center, D.G. Glaze and R.J. Schultz for following patients and facilitating sample collection; E.J.R. Dahle for previous research contributions; and A.L. Beaudet for discussions and critical review of the manuscript. This research was supported by the Howard Hughes Medical Institute and NIH grants HD24234 (H.Y.Z. and U.F.) and MRRC HD 24064, the International Rett Syndrome Association (R.A.), the Society for Gynecologic Investigation (I.V.) and the L.M. Chandler Research Fund (M.W.).
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Molecular Autism (2018)