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Population analysis of the alpha hemoglobin stabilizing protein (AHSP) gene identifies sequence variants that alter expression and function
Author(s) -
dos Santos Camila O.,
Zhou Suiping,
Secolin Rodrigo,
Wang Xiaomei,
Cunha Anderson F.,
Higgs Douglas R.,
Kwiatkowski Janet L.,
Thein Swee Lay,
Gallagher Patrick G.,
Costa Fernando F.,
Weiss Mitchell J.
Publication year - 2008
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.21041
Subject(s) - missense mutation , genetics , biology , gene , haplotype , fetal hemoglobin , mutation , asparagine , microbiology and biotechnology , allele , amino acid , pregnancy , fetus
α‐Hemoglobin stabilizing protein (AHSP) is a potential modifier of β‐thalassemia by virtue of its ability to detoxify excess free α‐globin. However, examination of patients with β‐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 α‐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 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 β‐thalassemia. Am. J. Hematol., 2008. © 2007 Wiley‐Liss, Inc.