PMID- 10508514
OWN - NLM
STAT- MEDLINE
DCOM- 19991019
LR  - 20220409
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 23
IP  - 2
DP  - 1999 Oct
TI  - Rett syndrome is caused by mutations in X-linked MECP2, encoding
      methyl-CpG-binding protein 2.
PG  - 185-8
AB  - Rett syndrome (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 movements. 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 males. 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.
FAU - Amir, R E
AU  - Amir RE
AD  - Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
FAU - Van den Veyver, I B
AU  - Van den Veyver IB
FAU - Wan, M
AU  - Wan M
FAU - Tran, C Q
AU  - Tran CQ
FAU - Francke, U
AU  - Francke U
FAU - Zoghbi, H Y
AU  - Zoghbi HY
LA  - eng
GR  - HD 24064/HD/NICHD NIH HHS/United States
GR  - HD242346/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (Chromosomal Proteins, Non-Histone)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MECP2 protein, human)
RN  - 0 (Methyl-CpG-Binding Protein 2)
RN  - 0 (Repressor Proteins)
RN  - 9007-49-2 (DNA)
SB  - IM
CIN - Nat Genet. 1999 Oct;23(2):127-8. PMID: 10508498
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - *Chromosomal Proteins, Non-Histone
MH  - DNA/chemistry/genetics
MH  - DNA Mutational Analysis
MH  - DNA-Binding Proteins/*genetics
MH  - Family Health
MH  - Female
MH  - Genetic Linkage
MH  - Humans
MH  - Male
MH  - Methyl-CpG-Binding Protein 2
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Pedigree
MH  - Point Mutation
MH  - *Repressor Proteins
MH  - Rett Syndrome/*genetics/pathology
MH  - Sequence Homology, Amino Acid
MH  - X Chromosome/*genetics
EDAT- 1999/10/03 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/10/03 09:00
PHST- 1999/10/03 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/10/03 09:00 [entrez]
AID - 10.1038/13810 [doi]
PST - ppublish
SO  - Nat Genet. 1999 Oct;23(2):185-8. doi: 10.1038/13810.