Population analysis of the alpha hemoglobin stabilizing protein (AHSP) gene identifies sequence variants that alter expression and function
Article first published online: 14 SEP 2007
Copyright © 2007 Wiley-Liss, Inc.
American Journal of Hematology
Volume 83, Issue 2, pages 103–108, February 2008
How to Cite
dos Santos, C. O., Zhou, S., Secolin, R., Wang, X., Cunha, A. F., Higgs, D. R., Kwiatkowski, J. L., Thein, S. L., Gallagher, P. G., Costa, F. F. and Weiss, M. J. (2008), Population analysis of the alpha hemoglobin stabilizing protein (AHSP) gene identifies sequence variants that alter expression and function. Am. J. Hematol., 83: 103–108. doi: 10.1002/ajh.21041
- Issue published online: 2 JAN 2008
- Article first published online: 14 SEP 2007
- Manuscript Accepted: 25 JUN 2007
- Manuscript Revised: 23 JUN 2007
- Manuscript Received: 1 JUN 2007
- The National Institutes of Health. Grant Numbers: R01-DK61692, R01-HL087427, R01-HL65448, UL1-RR-024134
- FAPESP. Grant Number: 02/13801-7
- CAPES. Grant Number: BEX0638/05-6
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 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 β-thalassemia. Am. J. Hematol., 2008. © 2007 Wiley-Liss, Inc.