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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-06-1623. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-06-1623v1 102/2/698    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Bekri, S. Articles by Bishop, D. F. Search for Related Content PubMed PubMed Citation Articles by Bekri, S. Articles by Bishop, D. F. Related Collections Hematopoiesis and Stem Cells Red Cells Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 July 2003, Vol. 102, No. 2, pp. 698-704 RED CELLS A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia Soumeya Bekri, Alison May, Philip D. Cotter, Ala I. Al-Sabah, Xiaojun Guo, Gillian S. Masters, and David F. Bishop From the Department of Human Genetics, Mount Sinai School of Medicine, New York, NY; the Laboratoire d'Hépato-Gastroentérologie et Nutrition-Faculté de Médecine de Nice, Centre Universitaire de Nice, Nice, France; and the Department of Haematology, University of Wales College of Medicine, Cardiff, United Kingdom X-linked sideroblastic anemia (XLSA) is caused by mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). XLSA was diagnosed in a 32-year-old woman with a mild phenotype and moderately late onset. Pyridoxine therapy had no effect in the proband, but in her affected son engendered a modest increase in hemoglobin concentration and a 4-fold reduction in ferritin iron. Molecular analysis identified a C to G transversion at nucleotide -206 from the transcription start site, as defined by primer extension, in the proximal promoter region of ALAS2. No other mutations were found in the promoter region, the flanking intronic sequences, the exons, or the 3' genomic region. The same mutation was found in her affected son but not in any other of her unaffected relatives. The mutation resulted in a 94% loss of activity relative to the wild-type sequence for a luciferase reporter construct containing the proximal 293 nucleotides (nt's) of the ALAS2 promoter when transfected into human erythroid K562 cells. Confirming the mutation's deleterious effect, the ALAS2 mRNA level in the proband's erythroid precursors was reduced 87%. The mutation occurred in or near 3 different putative transcription factor binding sites of unknown erythroid importance. The dramatic decreases in reporter activity and mRNA level suggest that the region of the mutation may bind a novel and important erythroid regulatory element. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Bose, C. Fugazza, M. Casalgrandi, A. Capelli, J. M. Cunningham, Q. Zhao, S. M. Jane, S. Ottolenghi, and A. Ronchi Functional Interaction of CP2 with GATA-1 in the Regulation of Erythroid Promoters Mol. Cell. Biol., May 15, 2006; 26(10): 3942 - 3954. [Abstract] [Full Text] [PDF] M. Schranzhofer, M. Schifrer, J. A. Cabrera, S. Kopp, P. Chiba, H. Beug, and E. W. Mullner Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis Blood, May 15, 2006; 107(10): 4159 - 4167. [Abstract] [Full Text] [PDF] J. C. Barton, P. L. Lee, L. F. Bertoli, and E. Beutler Iron Overload in an African American Woman with SS Hemoglobinopathy and a Promoter Mutation in the X-Linked Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 3683 - 3683. [Abstract]

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