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. 2001 Jul;38(7):435–442. doi: 10.1136/jmg.38.7.435

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

L Villard 1, N Levy 1, F Xiang 1, A Kpebe 1, V Labelle 1, C Chevillard 1, Z Zhang 1, C Schwartz 1, M Tardieu 1, J Chelly 1, M Anvret 1, M Fontes 1
PMCID: PMC1757181  PMID: 11432961

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.


Keywords: Rett syndrome; skewed X chromosome inactivation; X chromosome; MECP2

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Selected References

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