Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype

K. C. Hoffbuhr, L. M. Moses, M. A. Jerdonek, S. Naidu, E. P. Hoffman

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Rett syndrome is a neurodevelopmental disorder of early postnatal brain growth in girls. Patients show a normal neonatal period with subsequent developmental regression and a loss of acquired skills (communication and motor skills), deceleration of head growth, and development of typical hand stereotypies. Recent studies have shown that mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2) cause most typical cases of Rett syndrome. The MeCP2 gene encodes a protein that binds methylated cytosine residues of CpG dinucleotides and mediates, with histone deacetylases and transcriptional repressors, the transcription "silencing" of other genes. Girls with Rett syndrome exhibit mosaic expression for the MeCP2 defect at the cellular level, with most patients showing random X-inactivation and approximately equal numbers of cells expressing the normal MeCP2 gene and the mutated MeCP2 gene. In rare cases, females with a MeCP2 mutation escape phenotypic expression of the disorder because of nonrandom X-inactivation and the preferential inactivation of the mutated MeCP2 allele. Nonrandom patterns of X-inactivation may also contribute to the clinical variability often seen in girls with Rett syndrome. The spectrum of clinical phenotype caused by MeCP2 mutations is wide, including milder "preserved speech" variants, the severe congenital Rett variant, and a subset of X-linked recessive mental retardation in boys. Studies have shown that atypical and classical Rett syndrome can caused by the same MeCP2 mutations, indicating clinical phenotype is variable even among girls with the same MeCP2 mutation. The relationship between type of MeCP2 mutation, X-inactivation status, and clinical phenotype of Rett syndrome is complex and likely involves other environmental and polygenic modifiers.

Original languageEnglish (US)
Pages (from-to)99-105
Number of pages7
JournalMental Retardation and Developmental Disabilities Research Reviews
Issue number2
StatePublished - 2002


  • Atypical Rett syndrome
  • Genotype/phenotype
  • MeCP2
  • Rett syndrome
  • Skewed X-inactivation
  • X-inactivation

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neuropsychology and Physiological Psychology
  • Genetics(clinical)


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