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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-06-1623.
Submitted June 3, 2002
Accepted November 19, 2002
A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia
Soumeya Bekri, Alison May, Philip D Cotter, A I Al-Sabah, Xaiojun Guo, Gillian S Masters, and David F Bishop*
Department of Human Genetics, Mount Sinai School of Medicine, New York, NY, USA
Laboratoire d'Hepato-Gastroenterologie de Nutrition, Faculte de Medecine de Nice, Universitaire de Nice, Nice, France
Department of Haematology, University of Wales College of Medicine, Cardiff, Wales, United Kingdom
* Corresponding author; email: david.bishop{at}mssm.edu.
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 female 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 four-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 nt of the ALAS2 promoter when transfected into human erythroid K562 cells. Confirming the mutation's deleterious effect, ALAS2 mRNA level in the proband's erythroid precursors was reduced 87%. The mutation occurred in or near three 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.
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