Mutations in the methyl-CpG-binding protein 2 gene (MECP2) are identified in the majority of females with Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder. We searched for mutations by sequencing the MECP2 coding region in 45 sporadic cases (35 with classic RTT, eight with variant forms and two males) and in seven families with two or more affected females. Following our previous report of mutations in two families and eight sporadic cases [
], we here present 18 additional mutations. We found 13 single nucleotide substitutions, all of which are C→T transitions at CpG hot spots. Frameshift mutations, leading to premature termination of translation, include two single guanine (G) nucleotide deletions from a stretch of contiguous Gs, a novel four nucleotide deletion, a novel 32 nucleotide deletion in the C-terminal domain and a novel complex duplication/deletion rearrangement in the same region. When X-chromosome inactivation patterns were compared in 16 MECP2 mutation-positive and 23 mutation-negative samples, no significant differences were observed. The mutational spectrum in our subject population is similar to studies from around the world. Of over 300 MECP2 mutations reported, two-thirds are truncating mutations and one-third are missense mutations, mostly in the methyl-binding domain. Nearly 70% of all identified mutations are C→T transitions at one of eight CpG hot spots, and about 10% are intragenic deletions or complex rearrangements that lead to frameshifts in the C-terminal region. The rate of mutation detection in the MECP2 coding region ranges from 70 to 85% in clinically diagnosed RTT and is much lower in diagnostic variants.
- Wan M.
- Lee S.S.
- Zhang X.
- Houwink-Manville I.
- Song H.R.
- Amir R.E.
- et al.
Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotpots.
Am J Hum Genet. 1999; 65: 1520-1529
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- Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotpots.Am J Hum Genet. 1999; 65: 1520-1529
- Uber ein eigenartiges hirnatrophisches Syndrom bei Hyperammonamie im Kindesalter.Wien Med Wochenschr. 1966; 116: 723-738
- A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases.Ann Neurol. 1983; 14: 471-479
- Diagnostic criteria for Rett syndrome.Ann Neurol. 1988; 23: 425-428
- Rett syndrome: exclusion mapping following the hypothesis of germinal mosaicism for new X-linked mutations.Hum Genet. 1991; 86: 604-606
- Examination of X chromosome markers in Rett syndrome: exclusion mapping with a novel variation on multilocus linkage analysis.Am J Hum Genet. 1992; 50: 278-287
- A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map.Am J Hum Genet. 1997; 61: 634-641
- Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28.Am J Hum Genet. 1998; 63: 1552-1558
- Isolation, physical mapping, and northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2.Mamm Genome. 1996; 7: 533-535
- Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.Nat Genet. 1999; 23: 185-188
- MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin.Cell. 1997; 88: 471-481
- Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.Nature. 1998; 393: 386-389
- Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.Nat Genet. 1998; 19: 187-191
- Mutation screening in Rett syndrome patients.J Med Genet. 2000; 37: 250-255
- Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.Hum Mol Genet. 2000; 9 (published erratum appears in Hum Mol Genet 2000; 9(11):1717): 1119-1129
- Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.J Hum Genet. 2000; 45: 231-236
- MECP2 mutations account for most cases of typical forms of Rett syndrome.Hum Mol Genet. 2000; 9: 1377-1384
- Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.Hum Mol Genet. 2000; 9: 1369-1375
- Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes.Ann Neurol. 2000; 47: 670-679
- Rett syndrome: a surprising result of mutation in MECP2.Hum Mol Genet. 2000; 9: 2365-2375
- Two sisters with Rett syndrome.J Autism Dev Disord. 1990; 20: 129-138
- Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation.Am J Hum Genet. 1992; 51: 1229-1239
- Methyl-CpG-binding protein 2 mutations in Rett syndrome.Curr Opin Genet Dev. 2000; 10: 275-279
- Preserved speech variant is allelic of classic Rett syndrome.Eur J Hum Genet. 2000; 8: 325-330
- A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males.Am J Hum Genet. 2000; 67: 982-985
- MECP2 mutation in male patients with non-specific X-linked mental retardation.FEBS Lett. 2000; 481: 285-288
- Patterns of X chromosome inactivation in the Rett syndrome.Brain Dev. 1990; 12: 131-135
☆This paper was presented at the International Congress on Rett Syndrome, Karuizawa, Japan, in July 2000.
© 2001 Elsevier Science B.V. Published by Elsevier Inc. All rights reserved.