title: Alpha-haemoglobin stabilising protein is a quantitative trait gene that modifies the phenotype of beta-thalassaemia.
abstract: 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.
authors.affiliation: Molecular Haematology, Division of Gene and Cell Based Therapy, King's College London School of Medicine, London, UK.
authors.forename: Mei I
authors.initials: MI
authors.lastname: Lai
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Silver
authors.forename: Steve
authors.initials: S
authors.lastname: Best
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Mijovic
authors.forename: Stefano
authors.initials: S
authors.lastname: Colella
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Chad
authors.initials: C
authors.lastname: Garner
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Swee L
authors.initials: SL
authors.lastname: Thein
mesh_terms: D000328:Adult; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D005838:Genotype; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics; D012156:Reticulocytes / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics*
chemical_list: C468768:AHSP protein, human; D001798:Blood Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D005914:Globins