Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots
Open accessAbstract
Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C-->T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.
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Mutations in MECP2 account for 95% of typical RTT cases.
“It is now well established that mutations in MECP2 account for 95% of typical RTT cases and commonly occur de novo [36–38].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [37]
The Discussion (Mutation Detection) reports that MECP2 mutations were detected in approximately 50% of patients with RTT, not 95% of typical cases. It also says screening covered only the coding region, so that detection rate does not establish a contrary overall rate. The Abstract supports the link between MECP2 mutations and RTT, but not the claimed 95% figure. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRett syndrome is a neurological disorder caused by mutations in the X-linked gene MECP2.
“Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator.”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [37]
MECP2 mutations commonly occur de novo.
“It is now well established that mutations in MECP2 account for 95% of typical RTT cases and commonly occur de novo [36–38].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [37]
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- Authors
- Wan, M., Lee, S. S. J., Zhang, X., Houwink-Manville, I., Song, H.-R., Amir, R. E., Budden, S., Naidu, S., Pereira, J. L. P., Lo, I. F. M., Zoghbi, H. Y., Schanen, N. C., & Francke, U.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Baylor College of Medicine (US)
- Oregon Health & Science University (US)
- Kennedy Krieger Institute (US)
- Department of Health (CN)
- Corresponding author
- Francke, Uta
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 1999-12
- Volume
- 65
- Issue
- 6
- Pages
- 1520-1529
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1288362
- OpenAlex
- W2032474463
- Cited by
- 520
- References
- 1
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 9 · 2023: 4 · 2022: 12 · 2021: 14 · 2020: 15 · 2019: 13 · 2018: 11 · 2017: 8 · 2016: 22 · 2015: 9 · 2014: 11 · 2013: 20 · 2012: 17
- FWCI
- 25.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Center for Research Resources (RR 000 52, M01RR000052)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12 HD-034610, HD-24234, P01HD024448, HD24448)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- Rett syndrome, MECP2 mutations, MeCP2, de novo mutations, missense mutations, nonsense mutation, incontinentia pigmenti, X-inactivation skewing, male survival, phenotypic spectrum, neurodevelopmental disorders
- MeSH terms
- Alleles, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Dosage Compensation, Genetic, Female, Humans, Incontinentia Pigmenti, Male, Mosaicism, Mutation, Nuclear Family, Pedigree, Phenotype, Repressor Proteins, Genetic Variation, Rett Syndrome, Conserved Sequence, Germ-Line Mutation, Codon, Terminator, CpG Islands, DNA Methylation, Amino Acid Substitution, Methyl-CpG-Binding Protein 2
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