title: The first missense mutation causing Rett syndrome specifically affecting the MeCP2_e1 isoform.
abstract: We report the identification of the first de novo mutation at a highly conserved residue within the polyalanine stretch in the N-terminal region of the brain-dominant protein isoform MeCP2_e1 in a girl with classical Rett syndrome. The missense mutation, p.Ala2Val, leads to severe developmental delay, microcephaly, no language, severe epilepsy, and cognitive impairment. To evaluate the pathogenic potentials of the MECP2 mutation specific to the MeCP2_e1 isoform detected in this patient, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to generate a fusion protein with c-myc, and constructs were transfected in COS7 cells. In vitro studies demonstrated that, like wild-type MeCP2e_1, the N-terminal mutant is localized in the nucleus. Neither transcriptional nor translational effect on the MeCP2_e2 isoform was observed in fibroblasts from the p.Ala2Val patient, suggesting that MeCP2_e1 is involved in other functional process. These data suggest the important involvement of the N-terminus in the function of MeCP2 protein, and provide further evidence for the major impact of a specific MeCP2e_1 deficiency in the development of intellectual processing.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Fichou
authors.forename: Juliette
authors.initials: J
authors.lastname: Nectoux
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.forename: Haydeé
authors.initials: H
authors.lastname: Rosas-Vargas
authors.forename: Benoit
authors.initials: B
authors.lastname: Girard
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009690:Nucleic Acid Conformation; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015518:Rett Syndrome / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D020121:5' Untranslated Regions; D051783:Methyl-CpG-Binding Protein 2; D020033:Protein Isoforms; D012333:RNA, Messenger