Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the α-thalassemia myelodysplasia syndrome (ATMDS)

Abstract

Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. But many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects should reflect a wider spectrum of mutations because they are not prone to negative selection in development. It has been difficult to identify such mutations so far, but microarray analysis provides a new opportunity to do so. Using this approach, we have shown that in individuals with myelodysplasia associated with α-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene. These findings cast new light on this pleiotropic cofactor, which appears to be an essential component rather than a mere facilitator of globin gene expression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hematological analysis in individuals with ATMDS.
Figure 2: Gene expression analysis in an individual with ATMDS.
Figure 3: ATRX mutation analysis in individuals with ATMDS.
Figure 4: Abnormal splicing in individuals with ATMDS.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Higgs, D.R. et al. A review of the molecular genetics of the human α-globin gene cluster. Blood 73, 1081–1104 (1989).

    CAS  PubMed  Google Scholar 

  2. Gibbons, R.J. & Higgs, D.R. The molecular-clinical spectrum of the ATR-X syndrome. Am. J. Med. Genet. 97, 204–212 (2000).

    Article  CAS  Google Scholar 

  3. Gibbons, R.J., Picketts, D.J., Villard, L. & Higgs, D.R. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome). Cell 80, 837–845 (1995).

    Article  CAS  Google Scholar 

  4. McDowell, T.L. et al. Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes. Proc. Natl. Acad. Sci. USA 96, 13983–13988 (1999).

    Article  CAS  Google Scholar 

  5. Berube, N.G., Smeenk, C.A. & Picketts, D.J. Cell cycle-dependent phosphorylation of the ATRX protein correlates with changes in nuclear matrix and chromatin association. Hum. Mol. Genet. 9, 539–547 (2000).

    Article  CAS  Google Scholar 

  6. Weatherall, D.J. et al. Acquired haemoglobin H disease in leukaemia: pathophysiology and molecular basis. Br. J. Haematol. 38, 305–322 (1978).

    Article  CAS  Google Scholar 

  7. Higgs, D.R., Wood, W.G., Barton, C. & Weatherall, D.J. Clinical features and molecular analysis of acquired HbH disease. Am. J. Med. 75, 181–191 (1983).

    Article  CAS  Google Scholar 

  8. Higgs, D.R. & Bowden, D.K. Clinical and laboratory features of α-thalassemia syndromes. in Disorders of Hemoglobin (ed. Nagel, R.L.) 431–469 (Cambridge University Press, Cambridge, 2001).

    Google Scholar 

  9. Craddock, C.F. et al. Contrasting effects of α and β globin regulatory elements on chromatin structure may be related to their different chromosomal environments. EMBO J. 14, 1718–1726 (1995).

    Article  CAS  Google Scholar 

  10. Higgs, D.R., Sharpe, J.A. & Wood, W.G. Understanding α-globin gene expression: a step towards effective gene therapy. Semin. Hematol. 35, 93–104 (1998).

    CAS  PubMed  Google Scholar 

  11. Wilkie, A.O.M. et al. Clinical features and molecular analysis of the α-thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the α-globin complex. Am. J. Hum. Genet. 46, 1127–1140 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wada, T. & Gibbons, R.J. ATR-X syndrome. in Genetics and Genomics of Neurobehavioural Disorders (ed. Fisch, G.S.) 309–334 (Humana, Totowa, New Jersey, 2003).

    Chapter  Google Scholar 

  13. Krebs, J.E., Fry, C.J., Samuels, M.L. & Peterson, C.L. Global role for chromatin remodeling enzymes in mitotic gene expression. Cell 102, 587–598 (2000).

    Article  CAS  Google Scholar 

  14. Takeda, J. et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 73, 703–711 (1993).

    Article  CAS  Google Scholar 

  15. Nafa, K., Bessler, M., Castro-Malaspina, H., Jhanwar, S. & Luzzatto, L. The spectrum of somatic mutations in the PIG-A gene in paroxysmal nocturnal hemoglobinuria includes large deletions and small duplications. Blood Cells Mol. Dis. 24, 370–384 (1998).

    Article  CAS  Google Scholar 

  16. Happle, R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin. Genet. 29, 321–324 (1986).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Rose for help preparing the manuscript, A. Argentaro for allowing us to cite his unpublished data, C. Fisher for carrying out the hematology, the referring physicians M. Cook and A. Hendrick, the individuals with ATMDS for their participation, D. Weatherall for bringing this condition to our attention and for his continued support, and previous laboratory members C. Craddock, M. Vickers, C. Hatton and V. Barbour for important contributions to the description of ATMDS. The work was supported by the Medical Research Council and the Leukaemia Research Fund.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Douglas R Higgs.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gibbons, R., Pellagatti, A., Garrick, D. et al. Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the α-thalassemia myelodysplasia syndrome (ATMDS). Nat Genet 34, 446–449 (2003). https://doi.org/10.1038/ng1213

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1213

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing