Advertisement

X chromosome inactivation patterns in brain in Rett syndrome: implications for the disease phenotype

  • Joanne H. Gibson
    Affiliations
    Metabolic Diseases Research Unit, Western Sydney Genetics Program, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia

    School of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia
    Search for articles by this author
  • Sarah L. Williamson
    Affiliations
    Metabolic Diseases Research Unit, Western Sydney Genetics Program, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia

    School of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia
    Search for articles by this author
  • Susan Arbuckle
    Affiliations
    Department of Histopathology, Children's Hospital at Westmead, Sydney, NSW, Australia
    Search for articles by this author
  • John Christodoulou
    Correspondence
    Corresponding author. Tel.: +61 2 9845 3452; fax: +61 2 9845 1864.
    Affiliations
    Metabolic Diseases Research Unit, Western Sydney Genetics Program, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia

    School of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia
    Search for articles by this author

      Abstract

      Skewed X chromosome inactivation (XCI) has been implicated in modulating the severity of Rett syndrome (RTT), although studies by different groups have yielded conflicting results. In this study we have characterised the XCI pattern in various neuroanatomical regions of nine RTT brains and non-neural tissue in two of these patients to determine whether or not variable XCI patterns occur in different brain regions or somatic tissues of the same patient. The mean XCI patterns for frontal and occipital cortex were compared between RTT and control subjects, and showed no significant differences when comparing RTT frontal to control frontal cortex or RTT occipital to control occipital cortex. However, one RTT subject displayed variability across the different neuroanatomical regions of the brain and skewing in some non-neural tissues. This observation adds another dimension to the epigenetic factors that may contribute to the phenotype in RTT. It also mandates that caution should be exercised in factoring XCI, including assumptions based on the blood XCI pattern, into the development of phenotype–genotype correlations.

      Keywords

      Abbreviations:

      XCI (X chromosome inactivation), RTT (Rett syndrome), AR (androgen receptor), BSA (bovine serum albumin), GTP (guanine triphosphate), MBD (methyl-binding domain), TRD-NLS (transcription repressor domain - nuclear localisation signal)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ellaway C.
        • Christodoulou J.
        Rett syndrome: clinical characteristics and recent genetic advances.
        Disabil Rehabil. 2001; 23: 98-106
        • Amir R.E.
        • Van den Veyver I.B.
        • Wan M.
        • Tran C.Q.
        • Francke U.
        • Zoghbi H.Y.
        Rett Syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
        Nat Genet. 1999; 23: 185-188
        • Wan M.
        • Lee S.S.
        • Zhang X.
        • Houwink-Manville I.
        • Song H.R.
        • Amir R.E.
        • et al.
        Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.
        Am J Hum Genet. 1999; 65: 1520-1529
        • Amir R.E.
        • Zoghbi H.Y.
        Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype–genotype correlations.
        Am J Med Genet. 2000; 97: 147-152
        • Bienvenu T.
        • Carrié A.
        • de Roux N.
        • Vinet M-C.
        • Jonveaux P.
        • Couvert P.
        • et al.
        MECP2 mutations account for most cases of typical forms of Rett syndrome.
        Hum Mol Genet. 2000; 9: 1377-1384
        • Dragich J.
        • Houwink-Manville I.
        • Schanen C.
        Rett syndrome: a surprising result of mutation in MECP2.
        Hum Mol Genet. 2000; 9: 2365-2375
        • Hampson K.
        • Woods C.G.
        • Latif F.
        • Webb T.
        Mutations in the MECP2 gene in a cohort of girls with Rett syndrome.
        J Med Genet. 2000; 37: 610-612
        • Huppke P.
        • Laccone F.
        • Krämer N.
        • Engel W.
        • Hanefeld F.
        Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.
        Hum Mol Genet. 2000; 9: 1369-1375
        • Obata K.
        • Matsuishi T.
        • Yamashita Y.
        • Fukuda T.
        • Kuwajima K.
        • Horiuchi I.
        • et al.
        Mutation analysis of the methyl-CpG binding protein 2 gene (MECP2) in patients with Rett syndrome.
        J Med Genet. 2000; 37: 608-610
        • Hoffbuhr K.C.
        • Moses L.M.
        • Jerdonek M.A.
        • Naidu S.
        • Hoffman E.P.
        Associations between MECP2 mutations, X-chromosome inactivation, and phenotype.
        Ment Retard Dev Disabil Res Rev. 2002; 8: 99-105
        • Weaving L.S.
        • Williamson S.L.
        • Bennetts B.
        • Davis M.
        • Ellaway C.J.
        • Leonard H.
        • et al.
        Effects of MECP2 mutation type, location and x-inactivation in modulating Rett syndrome phenotype.
        Am J Med Genet. 2003; 118A: 103-114
        • Armstrong D.
        • Dunn J.K.
        • Antalffy B.
        • Trivedi R.
        Selective dendritic alterations in the cortex of Rett syndrome.
        J Neuropathol Exp Neurol. 1995; 54: 195-201
        • Armstrong D.D.
        Rett syndrome neuropathology review 2000.
        Brain Dev. 2001; 23: 72-76
        • Armstrong D.D.
        Neuropathology of Rett syndrome.
        Ment Retard Dev Disabil Res Rev. 2002; 8: 72-76
        • Plenge R.M.
        • Stevenson R.A.
        • Lubs H.A.
        • Schwartz C.E.
        • Willard H.F.
        Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders.
        Am J Hum Genet. 2002; 71: 168-173
        • Amir R.E.
        • Van den Veyver I.B.
        • Schultz R.
        • Malicki D.M.
        • Tran C.Q.
        • Dahle E.J.
        • et al.
        Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes.
        Ann Neurol. 2000; 47: 670-679
        • Van den Veyver I.B.
        • Zoghbi H.Y.
        Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome.
        Brain Dev. 2001; 23: 147-151
        • Ishii T.
        • Makita Y.
        • Ogawa A.
        • Amamiya S.
        • Yamamoto M.
        • Miyamoto A.
        • et al.
        The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome.
        Brain Dev. 2001; 23: 161-164
        • Sirianni N.
        • Naidu S.
        • Pereira J.
        • Pillotto R.F.
        • Hoffman E.P.
        Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28.
        Am J Hum Genet. 1998; 63: 1552-1558
        • Hoffbuhr K.
        • Devaney J.M.
        • LaFleur B.
        • Sirianni N.
        • Scacheri C.
        • Giron J.
        • et al.
        MeCP2 mutations in children with and without the phenotype of Rett syndrome.
        Neurology. 2001; 56: 1486-1495
        • Villard L.
        • Lévy N.
        • Xiang F.
        • Kpebe A.
        • Labelle V.
        • Chevillard C.
        • 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.
        J Med Genet. 2001; 38: 435-442
        • Zoghbi H.Y.
        • Percy A.K.
        • Schultz R.J.
        • Fill C.
        Patterns of X chromosome inactivation in the Rett syndrome.
        Brain Dev. 1990; 12: 131-135
        • Anvret M.
        • Wahlström J.
        Rett syndrome: random X chromosome inactivation.
        Clin Genet. 1994; 45: 274-275
        • LaSalle J.M.
        • Goldstine J.
        • Balmer D.
        • Greco C.M.
        Quantitative localization of heterogeneous methyl-CpG-binding protein 2 (MeCP2) expression phenotypes in normal and Rett syndrome brain by laser scanning cytometry.
        Hum Mol Genet. 2001; 10: 1729-1740
        • Shahbazian M.D.
        • Sun Y.
        • Zoghbi H.Y.
        Balanced X chromosome inactivation patterns in the Rett syndrome brain.
        Am J Med Genet. 2002; 111: 164-168
        • Sambrook J.
        • Russell D.W.
        3rd ed. Molecular cloning, a laboratory manual. vol. 1. Cold Spring Harbor Laboratory Press, New York2001
        • Allen R.C.
        • Zoghbi H.Y.
        • Moseley A.B.
        • Rosenblatt H.M.
        • Belmont J.W.
        Methylation of HpaII and HhaI Sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation.
        Am J Hum Genet. 1992; 51: 1229-1239
        • Nomura Y.
        • Segawa M.
        • Hasegawa M.
        Rett syndrome—clinical studies and pathophysiological consideration.
        Brain Dev. 1984; 6: 475-486
        • Balmer D.
        • Arredondo J.
        • Samaco R.C.
        • LaSalle J.M.
        MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain.
        Hum Genet. 2002; 110: 545-552
        • Young J.I.
        • Zoghbi H.Y.
        X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of Rett syndrome.
        Am J Hum Genet. 2004; 74: 511-520