Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome withoutMECP2 mutation: implications for the disease
- Laurent Villarda,
- Nicolas Lévya,b,
- Fengqing Xiangc,
- Arlette Kpebea,
- Véronique Labelleb,
- Christophe Chevillardd,
- Zhiping Zhangc,e,
- Charles E Schwartza,f,
- Marc Tardieug,h,
- Jamel Chellyi,
- Maria Anvretc,e,
- Michel Fontèsa
- aINSERM U491, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France, bDépartement de Génétique Médicale, Laboratoire de Génétique Moléculaire, Hôpital d'Enfants de la Timone, 13385 Marseille Cedex 5, France, cDepartment of Clinical Neuroscience and Molecular Medicine, Karolinska Hospital, SE-171 76 Stockholm, Sweden, dINSERM U399, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France, eDepartment of Molecular Sciences, AstraZeneca R&D, Södertälje, SE-151 85 Södertälje, Sweden, fGreenwood Genetic Center, Greenwood, South Carolina 29646, USA, gService de Neurologie Pédiatrique, Hôpital du Kremlin Bicêtre, Paris, France, hCRI INSERM 96012, Université Paris Sud, France, iINSERM U129, CHU Cochin-Port-Royal, 75014 Paris, France
- Dr Fontès,Michel.Fontes{at}medecine.univ-mrs.fr
- Revised 29 March 2001
- Accepted 17 April 2001
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 theMECP2 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 inMECP2 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.
