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Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation

Nature Genetics volume 24, pages 368371 (2000) | Download Citation



A goal of molecular genetics is to understand the relationship between basic nuclear processes, epigenetic changes and the numerous proteins that orchestrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated proteins, and a carboxy-terminal domain which identifies it as a member of the SNF2 family of helicase/ATPases1,2. Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and α-thalassaemia1. This circumstantial evidence suggests that ATRX may act as a transcriptional regulator through an effect on chromatin. We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus. Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes3. Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings provide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.

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We thank W.R.A. Brown and D. Jackson for probes; M. Valdivia for anti-UBF antibodies; V.J. Buckle for helpful advice; D. Jackson for probes to detect the human ribosomal DNA arrays; T. Jones and I. Smith for help with the analysis of methylcytosine levels using HPLC; and D.J. Weatherall for support and encouragement. The work was supported by the MRC, the Wellcome Trust (R.J.G.), Action Research (D.M.O.) and the C.J. Marin Travelling Fellowship (D.G.).

Author information


  1. MRC Molecular Haematology Unit, Institute of Molecular Medicine, Oxford, UK.

    • Tarra L. McDowell
    • , Delia M. O'Rourke
    • , David Garrick
    • , Helena Ayyub
    •  & Douglas R. Higgs
  2. Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.

    • Richard J. Gibbons
    •  & Sundhya Raman


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Correspondence to Douglas R. Higgs.

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