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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2019-2026. Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-09-3360. This Article Full Text (PDF) All Versions of this Article: 2003-09-3360v1 103/6/2019    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Steensma, D. P Articles by Gibbons, R. J Search for Related Content PubMed PubMed Citation Articles by Steensma, D. P Articles by Gibbons, R. J Social Bookmarking                   What's this? Submitted September 30, 2003 Accepted October 24, 2003 Acquired somatic ATRX mutations in myelodysplastic syndrome associated with thalassemia (ATMDS) convey a more severe hematological phenotype than germline ATRX mutations David P Steensma*, Douglas R Higgs, Chris A Fisher, and Richard J Gibbons MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom * Corresponding author; email: steensma.david{at}mayo.edu. Acquired somatic mutations in ATRX, an X-linked gene encoding a chromatin-associated protein, were recently identified in four patients with the rare subtype of myelodysplastic syndrome (MDS) associated with thalassemia (ATMDS). Here we describe a series of novel point mutations in ATRX detected in archival DNA samples from marrow and/or blood of patients with ATMDS by use of denaturing high performance liquid chromatography (DHPLC), a technique sensitive to low-level mosaicism. Two of the new mutations result in changes in amino acids altered in previously described pedigrees with germline ATRX mutations (ATR-X syndrome), but the hematological abnormalities were much more severe in the ATMDS patients than in the corresponding constitutional cases. In one ATMDS case where DNA samples from several time points were available, the proportion of ATRX-mutant subclones correlated with changes in the amount of hemoglobin H. This study strengthens the link between acquired, somatic ATRX mutations and ATMDS, illustrates how molecular defects associated with MDS and other hematological malignancies masked by somatic mosaicism may be detected by DHPLC, and shows that additional factors increase the severity of the hematological phenotype of ATRX mutations in ATMDS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. D. Phillips, D. P. Steensma, M. A. Pulsipher, G. J. Spangrude, and J. P. Kushner Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria Blood, March 15, 2007; 109(6): 2618 - 2621. [Abstract] [Full Text] [PDF] P. S. Haas, M. Schwabe, C. Fisher, R. Gibbons, D. R. Higgs, E. Bisse, and M. Lubbert Two Novel Somatic Mutations of the ATRX Gene in Female Patients with Acquired Alpha Thalassemia of Myelodysplastic Syndrome (ATMDS). Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 1765 - 1765. [Abstract] [PDF] D. P. Steensma JAK2 V617F in Myeloid Disorders: Molecular Diagnostic Techniques and Their Clinical Utility: A Paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology J. Mol. Diagn., September 1, 2006; 8(4): 397 - 411. [Abstract] [Full Text] [PDF] R. G. Goodwin, W. J. Kell, P. Laidler, C. C. Long, S. D. Whatley, M. McKinley, M. N. Badminton, A. K. Burnett, G. T. Williams, and G. H. Elder Photosensitivity and acute liver injury in myeloproliferative disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene in hematopoietic cells Blood, January 1, 2006; 107(1): 60 - 62. [Abstract] [Full Text] [PDF] D. P. Steensma and A. F. List Genetic Testing in the Myelodysplastic Syndromes: Molecular Insights Into Hematologic Diversity Mayo Clin. Proc., May 1, 2005; 80(5): 681 - 698. [Abstract] [PDF] D. P. Steensma, R. J. Gibbons, and D. R. Higgs Acquired {alpha}-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies Blood, January 15, 2005; 105(2): 443 - 452. [Abstract] [Full Text] [PDF] D. P. Steensma, R. J. Gibbons, R. A. Mesa, A. Tefferi, and D. R. Higgs Somatic Point Mutations in RUNX1/CBFA2/AML1 Are Common in High-Risk Myelodysplastic Syndrome, but Not in Myelofibrosis with Myeloid Metaplasia. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 2438 - 2438. [Abstract] D. P. Steensma, S. L. Allen, R. J. Gibbons, C. A. Fisher, and D. R. Higgs A Novel Splicing Mutation in the Gene Encoding the Chromatin-Associated Factor ATRX Associated with Acquired Hemoglobin H Disease in Myelodysplastic Syndrome (ATMDS). Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 3606 - 3606. [Abstract] D. R. Higgs Ham-Wasserman Lecture: Gene Regulation in Hematopoiesis: New Lessons from Thalassemia Hematology, January 1, 2004; 2004(1): 1 - 13. [Abstract] [Full Text] [PDF]

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