Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 133, Issue 6, Pages 675-682Publisher
WILEY
DOI: 10.1111/j.1365-2141.2006.06075.x
Keywords
alpha-haemoglobin stabilising protein; quantitative trait; genotype/phenotype; beta-thalassaemia
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Funding
- Medical Research Council [G0000111] Funding Source: researchfish
- MRC [G0000111] Funding Source: UKRI
- Medical Research Council [G0000111] Funding Source: Medline
- NIDDK NIH HHS [R01 DK061692] Funding Source: Medline
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It has been suggested that altered levels or function of alpha-haemoglobin stabilising protein (AHSP), an erythroid-specific protein that binds specifically to free alpha-(haemo)globin, might account for some of the clinical variability in beta-thalassaemia. To assess the variation of AHSP expression, mRNA levels in circulating reticulocytes of 103 healthy individuals were measured by quantitative reverse transcription-polymerase chain reaction. AHSP expression varied up to threefold, and did not correlate with age or sex. A systematic survey of the AHSP locus identified eight sequence variants, of which six were common. Four common variants, including the longer homopolymer (T18) in the putative promoter, are strongly associated with AHSP expression. Reporter assays in K562 cells showed that the activity of the shorter (T15) reporter was relatively lower than that of the T18 reporter. In a study of nine anaemic patients who were heterozygous for beta-thalassaemia and also heterozygous for the triplicated alpha-globin gene (alpha alpha alpha/alpha alpha), frequency of the shorter homopolymer was higher than expected. AHSP expression is variable, with cis control accounting for some of its variance. In some families, the subtle altered levels in AHSP related to the AHSP genotype appears to be a relevant contributory factor in the haematological phenotype.
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