Nature Genetics
23, 185 - 188 (1999)
doi:10.1038/13810
Rett syndrome is caused by mutations in X-linked MECP2, encoding
methyl-CpG-binding protein 2Ruthie E. Amir1, Ignatia B. Van den Veyver2, 3, Mimi Wan5, Charles Q. Tran3, Uta Francke5, 6
& Huda Y. Zoghbi1, 2, 41
Department of Pediatrics, Baylor College of Medicine,
Houston, Texas 77030, USA.
2
Department of Molecular and Human Genetics, Baylor
College of Medicine, Houston, Texas 77030,
USA. 3
Department of Obstetrics and Gynecology, Baylor College
of Medicine, Houston, Texas 77030,
USA. 4
Howard Hughes Medical Institute, Baylor College of
Medicine, Houston, Texas 77030,
USA. 5
Department of Genetics, Stanford University School
of Medicine, Stanford, California 94305,
USA. 6
Howard Hughes Medical Institute, Stanford University
School of Medicine, Stanford, California 94305
, USA.
Correspondence should be addressed to Huda Y. Zoghbi hzoghbi@bcm.tmc.eduRett 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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