title: Population analysis of the alpha hemoglobin stabilizing protein (AHSP) gene identifies sequence variants that alter expression and function.
abstract: 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 12391A 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.
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Camila O
authors.initials: CO
authors.lastname: dos Santos
authors.forename: Suiping
authors.initials: S
authors.lastname: Zhou
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Secolin
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.forename: Anderson F
authors.initials: AF
authors.lastname: Cunha
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.forename: Janet L
authors.initials: JL
authors.lastname: Kwiatkowski
authors.forename: Swee Lay
authors.initials: SL
authors.lastname: Thein
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D019943:Amino Acid Substitution; D001798:Blood Proteins / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics; D005786:Gene Expression Regulation; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013789:Thalassemia / Q000235:genetics; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: C468768:AHSP protein, human; D001798:Blood Proteins; D018832:Molecular Chaperones; D004247:DNA