Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease

J Med Genet. 2001 Jul;38(7):435-42. doi: 10.1136/jmg.38.7.435.

Abstract

Background: Rett syndrome is a neurodevelopmental disorder affecting only girls; 99.5% of Rett syndrome cases are sporadic, although several familial cases have been reported. Mutations in the MECP2 gene were identified in approximately 70-80% of sporadic Rett syndrome cases.

Methods: We have screened the MECP2 gene coding region for mutations in five familial cases of Rett syndrome and studied the patterns of X chromosome inactivation (XCI) in each girl.

Results: We found a mutation in MECP2 in only one family. In the four families without mutation in MECP2, we found that (1) all mothers exhibit a totally skewed pattern of XCI; (2) six out of eight affected girls also have a totally skewed pattern of XCI; and (3) it is the paternally inherited X chromosome which is active in the patients with a skewed pattern of XCI. Given that the skewing of XCI is inherited in our families, we genotyped the whole X chromosome using 32 polymorphic markers and we show that a locus potentially responsible for the skewed XCI in these families could be located on the short arm of the X chromosome.

Conclusion: These data led us to propose a model for familial Rett syndrome transmission in which two traits are inherited, an X linked locus abnormally escaping X chromosome inactivation and the presence of a skewed XCI in carrier women.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Chromosomal Proteins, Non-Histone*
  • Chromosome Segregation / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Dosage Compensation, Genetic*
  • Female
  • Fragile X Mental Retardation Protein
  • Genetic Testing
  • Haplotypes / genetics
  • Humans
  • Male
  • Methyl-CpG-Binding Protein 2
  • Models, Genetic*
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nuclear Family
  • Pedigree
  • Polymorphism, Genetic / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • RNA-Binding Proteins*
  • Receptors, Androgen / genetics
  • Repressor Proteins*
  • Rett Syndrome / genetics*
  • X Chromosome / genetics*

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • FMR1 protein, human
  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Androgen
  • Repressor Proteins
  • Fragile X Mental Retardation Protein