Advertisement

The role of X-chromosome inactivation in the manifestation of Rett syndrome

      Abstract

      X-chromosome inactivation (XCI) is random in the majority of patients with classical Rett syndrome (RTT). Preferential inactivation of the X chromosome with the mutated MECP2 gene is found in mildly symptomatic or asymptomatic carrier females. These findings lead to a hypothesis that random XCI is causally involved in the pathogenesis of RTT in heterozygous females. It is the cluster of functionally defective nerve cells lacking fully functional MeCP2 generated by inactivation of normal MECP2 allele that causes the wide spectrum of RTT symptoms. Thus, RTT is a rare human disease manifestation which is triggered most probably by random XCI.

      Keywords

      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

        • Nan X.
        • Canpoy J.
        • Bird A.
        MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin.
        Cell. 1997; 88: 471-481
        • Amir R.E.
        • Van den Veyver I.B.
        • Wan M.
        • Tran C.G.
        • 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
        • Van den Veyver I.B.
        • Zoghbi H.Y.
        Methyl-CpG-binding protein 2 mutations in Rett syndrome.
        Curr Opin Genet Dev. 2000; 10: 275-279
        • Shanen C.
        • Francke U.
        A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map.
        Am J Hum Genet. 1998; 63: 267-269
        • 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
        • Huppke P.
        • Laccone F.
        • Kramer N.
        • Engel W.
        • Hanefeld F.
        Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.
        Hum Mol Genet. 2000; 9: 1369-1375
        • Bienvenu T.
        • Carrie A.
        • de Roux N.
        • Vinet M.-C.
        • Jonieaux P.
        • Couvert P.
        • et al.
        MECP2 mutations account for most cases of typical forms of Rett syndrome.
        Hum Mol Genet. 2000; 9: 1377-1384
        • Tate P.
        • Skarnes W.
        • Bird A.
        The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse.
        Nat Genet. 1996; 12: 205-208
        • 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
        • Lyon M.F.
        Gene action in the X-chromosome of the mouse (Mus musculus L.).
        Nature. 1961; 190: 372-373
        • Rastan S.
        Non-random X chromosome inactivation in mouse X-autosome translocation embryos – location of the X inactivation centre.
        J Embryol Exp Morphol. 1983; 78: 1-22
        • Brown C.J.
        • Lafreniere R.G.
        • Powers V.E.
        • Sebastio G.
        • Ballabio A.
        • Pettigrew C.
        • et al.
        Localization of the X inactivation center on the human X chromosome in Xq13.
        Nature. 1991; 349: 82-84
        • Heard E.
        • Clerc P.
        • Avner P.
        X-chromosome inactivation in mammals.
        Annu Rev Genet. 1997; 31: 571-610
        • Brown C.J.
        • Ballabio A.
        • Ruppert J.L.
        • Lafreniere R.G.
        • Xing Y.
        • Lawrence C.
        • et al.
        A gene from the region of the human X-inactivation center is expressed exclusively from the inactive X chromosome.
        Nature. 1991; 349: 38-44
        • Lee J.T.
        • Strauss W.M.
        • Dausman J.A.
        • Jaenisch R.
        A 450 kb transgene displays properties of the mammalian X-inactivation center.
        Cell. 1996; 86: 83-94
        • Lee J.T.
        • Jaenisch R.
        Long range cis effects of ectopic X-inactivation centers on a mouse autosome.
        Nature. 1997; 386: 275-279
        • Herzing L.B.K.
        • Romer J.T.
        • Horn J.M.
        • Ashworth A.
        Xist has properties of the X-chromosome inactivation centre.
        Nature. 1997; 386: 272-275
        • Heard E.
        • Mongelard F.
        • Arnaud D.
        • Avner P.
        Xistyeast artificial chromosome transgenes function as X-inactivation centers only in multicopy arrays and not as single copies.
        Mol Cell Biol. 1999; 19: 3156-3166
        • Heard E.
        • Mongelard F.
        • Arnaud D.
        • Chureau C.
        • Vour'c C.
        • Avner P.
        Human Xist yeast artificial chromosome transgenes show partial X inactivation center function in mouse embryonic stem cells.
        Proc Natl Acad Sci USA. 1999; 96: 6841-6846
        • Penny G.D.
        • Kay G.F.
        • Sheardown S.A.
        • Rastan S.
        • Brockdorff N.
        Requirement for Xist in the X chromosome inactivation.
        Nature. 1996; 379: 131-137
        • Marahrens Y.
        • Panning B.
        • Dausman J.
        • Strauss W.
        • Jaenisch R.
        Xist-deficient mice are defective in dosage compensation but not spermatogenesis.
        Genes Dev. 1997; 11: 156-166
        • Takagi N.
        • Sasaki M.
        Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse.
        Nature. 1975; 256: 640-642
        • West J.D.
        • Frels W.I.
        • Chapman V.M.
        • Papaioannou V.E.
        Preferential expression of the maternally derived X chromosome in the mouse yolk sac.
        Cell. 1977; 12: 873-882
        • Clemson C.M.
        • McNeil J.A.
        • Willard H.F.
        • Lawrence J.B.
        XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure.
        J Cell Biol. 1996; 132: 259-275
        • Disteche C.M.
        Escape from X inactivation in human and mouse.
        Trends Genet. 1995; 11: 17-22
        • Carrel L.
        • Cottle A.A.
        • Goglin K.C.
        • Willard H.F.
        A first-generation X-inactivation profile of the human X chromosome.
        Proc Natl Acad Sci USA. 1999; 96: 14440-14444
        • Takagi N.
        Preferential inactivation of the paternally derived X chromosome in mice.
        in: Russell L.B. Genetic mosaics and chimeras in mammals. Plenum, New York1978: 341-360
        • Cattanach V.M.
        A chemically-induced variegation-type position effect in the mouse.
        Z Vererbugsl. 1961; 92: 165-182
        • Nesbitt M.N.
        • Gartler S.M.
        The applications of genetic mosaicism to developmental problems.
        Annu Rev Genet. 1971; 5: 143-162
        • Naumova A.K.
        • Plenge R.M.
        • Bird L.M.
        • Leppert M.
        • Morgan K.
        • Willard H.F.
        • et al.
        Heritability of X chromosome inactivation phenotype in a large family.
        Am J Hum Genet. 1996; 58: 1111-1119
        • Johnston P.G.
        • Cattanach B.M.
        Controlling elements in the mouse. IV. Evidence of non-random X-inactivation.
        Genet Res. 1981; 37: 151-160
        • Simmler M.C.
        • Cattanach B.M.
        • Rasberry C.
        • Rougeulle C.
        • Avner P.
        Mapping the murine Xce locus with (CN)n repeats.
        Mamm Genome. 1993; 4: 515-526
        • Ogura H.
        • Takada S.
        • Mise N.
        • Sugimoto M.
        • Tan S.-S.
        • Takagi N.
        Translocation breakpoint possibly predisposes to nonrandom X-chromosome inactivation in mouse embryos bearing Searle's T(X;16)16H translocation.
        Cytogenet Cell Genet. 1998; 80: 173-178
        • Plenge R.M.
        • Hendrich B.D.
        • Schwartz C.
        • Arena J.F.
        • Naumova A.
        • Sapienza C.
        • et al.
        A promoter mutation in the XIST gene in two families with skewed X-chromosome inactivation.
        Nat Genet. 1996; 17: 353-356
        • Greer W.L.
        • Kwong P.C.
        • Peacocke M.
        • Ip P.
        • Rubin L.A.
        • Siminovitch K.A.
        X-chromosome inactivation in the Wiskott–Aldrich syndrome: a marker for detection of the carrier state and identification of cell lineages expressing the gene defect.
        Genomics. 1989; 4: 60-67
        • Puck J.M.
        • Nussbaum R.L.
        • Conley M.E.
        Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation.
        J Clin Invest. 1987; 79: 1359-1400
        • Fearon E.R.
        • Winkelstein J.A.
        • Civin C.I.
        • Pardoll D.M.
        • Vogelstein B.
        Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome.
        N Engl J Med. 1987; 316: 427-431
        • Gale R.E.
        • Wheadon H.
        • Boulos P.
        • Linch D.C.
        Tissue specificity of X-chromosome inactivation patterns.
        Blood. 1994; 83: 2899-2905
        • Guy J.
        • Hendrich B.
        • Holmes M.
        • Martin J.E.
        • Bird A.
        A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.
        Nat Genet. 2001; 26: 322-326
        • Chen R.Z.
        • Akbarian S.
        • Tudor M.
        • Jaenisch R.
        Deficiency of methyl-CpG binding protein-2 in CNS neuron results in a Rett-like phenotype in mice.
        Nat Genet. 2001; 27: 327-331
        • Zoghbi H.Y.
        • Percey A.K.
        • Schultz R.J.
        • Fill C.
        Patterns of X chromosome inactivation in the Rett syndrome.
        Brain Dev. 1990; 12: 131-135