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

Laurent Villard (1) , Nicolas Lévy (1, 2) , Fengqing Xiang (3) , Arlette Kpebe (1) , Véronique Labelle (2) , Christophe Chevillard (4, 5) , Zhiping Zhang (3, 6) , Charles E Schwartz (1, 7) , Marc Tardieu (8, 9) , Jamel Chelly (10) , Maria Anvret (3, 6) , Michel Fontes (1)

1 Département de génétique médicale [Hôpital de la Timone - APHM]
2 Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM]
3 Department of Clinical Neuroscience and Molecular Medicine [Stockholm, Sweden]
4 Faculté de Médecine - Laboratoire de Parasitologie-Mycologie [AP-HM Hôpital de la Timone]
5 IGMP - U399 Inserm - AMU - Immunologie et Génétique des Maladies Parasitaires [Aix Marseille Université]
6 Department of Molecular Sciences [Södertälje, Sweden]
7 Greenwood Genetic Center [Greenwood, South Carolina, USA]
8 Service de Neurologie Pédiatrique [CHU Bicêtre]
9 Régulation de la réponse immune, infection VIH-1 et autoimmunité
10 Génétique et pathologie moléculaires

Background—Rett syndrome is a neurodevelopmental disorder a Vecting 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 a Vected 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: Skewed X-inactivation; X chromosome; MECP2; Rett syndrome

Domains: Life Sciences [q-bio]; Microbiology and Parasitology

Laurent Villard, Nicolas Lévy, Fengqing Xiang, Arlette Kpebe, Véronique Labelle, et al.. Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease. Journal of Medical Genetics, 2001, 38 (7), pp.435-442. ⟨10.1136/jmg.38.7.435⟩. ⟨hal-01593090⟩