Journal
AMERICAN JOURNAL OF HEMATOLOGY
Volume 83, Issue 2, Pages 103-108Publisher
WILEY-LISS
DOI: 10.1002/ajh.21041
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Funding
- Medical Research Council [MC_U137961144] Funding Source: Medline
- NCRR NIH HHS [UL1-RR-024134] Funding Source: Medline
- NHLBI NIH HHS [R01-HL087427, R01-HL65448] Funding Source: Medline
- NIDDK NIH HHS [R01 DK061692, R01-DK61692] Funding Source: Medline
- Medical Research Council [MC_U137961144] Funding Source: researchfish
- MRC [MC_U137961144] Funding Source: UKRI
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alpha-Hemoglobin stabilizing protein (AHSP) is a potential modifier of beta-thalassemia by virtue of its ability to detoxify excess free alpha-globin. However, examination of patients with beta-thalassemia from a few geographic regions failed to identify obvious AHSP mutations. We extended these studies by analyzing AHSP gene sequences in 366 anonymous individuals from five different areas of the world. We detected numerous polymorphisms comprising 18 different haplotypes and two rare missense mutations. Two sequence variations produce functional effects in laboratory assays. First, a rare missense mutation in a Brazilian/Mediterranean cohort converts asparagine to isoleucine at position 75 of AHSP protein and impairs its ability to inhibit reactive oxygen species production by alpha-hemoglobin. Second, a high-frequency polymorphism in intron 1 of the AHSP gene (12391 G>A) alters an Oct-1 transcription factor binding site previously shown to be important for optimal gene expression. The 12391 (A) under bar polymorphism impairs Oct-1 binding and inhibits the ability of AHSP regulatory sequences to activate expression of a linked luciferase reporter. Although structural mutations predicted to alter AHSP protein function or ablate its activity are rare, the 12391 G>A SNP is common and represents a potential mechanism through which genetically determined variations in AHSP expression could influence beta-thalassemia.
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