151. Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease
- Author
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Jamel Chelly, Fengqing Xiang, Charles E. Schwartz, Zhiping Zhang, Marc Tardieu, Arlette Kpebe, Laurent Villard, Véronique Labelle, Christophe Chevillard, Michel Fontes, Maria Anvret, Nicolas Lévy, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Neuroscience and Molecular Medicine [Stockholm, Sweden], Karolinska University Hospital [Stockholm], Laboratoire de Parasitologie-Mycologie [AP-HM Hôpital de la Timone] (Faculté de Médecine), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Immunologie et Génétique des Maladies Parasitaires [Aix Marseille Université] (IGMP - U399 Inserm - AMU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Molecular Sciences [Södertälje, Sweden], AstraZeneca R&D [Södertälje, Sweden], Greenwood Genetic Center [Greenwood, South Carolina, USA], Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et pathologie moléculaires, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de parasitologie-mycologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), and Spinelli, Lionel
- Subjects
Male ,X Chromosome ,Chromosomal Proteins, Non-Histone ,Methyl-CpG-Binding Protein 2 ,DNA Mutational Analysis ,Rett syndrome ,Locus (genetics) ,Nerve Tissue Proteins ,Biology ,X-inactivation ,MECP2 ,Nuclear Family ,03 medical and health sciences ,Fragile X Mental Retardation Protein ,0302 clinical medicine ,Neurodevelopmental disorder ,Chromosome Segregation ,Dosage Compensation, Genetic ,Genetics ,medicine ,Rett Syndrome ,Humans ,Genetic Testing ,RNA, Messenger ,Skewed X-inactivation ,[SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology ,Genetics (clinical) ,X chromosome ,Alleles ,030304 developmental biology ,0303 health sciences ,Polymorphism, Genetic ,Models, Genetic ,Haplotype ,RNA-Binding Proteins ,Original Articles ,medicine.disease ,Pedigree ,DNA-Binding Proteins ,Repressor Proteins ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Haplotypes ,Receptors, Androgen ,Mutation ,Female ,030217 neurology & neurosurgery - 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
- Published
- 2001