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Analysis of alpha hemoglobin stabilizing protein overexpression in murine β‐thalassemia
Author(s) -
Nasimuzzaman Md,
Khandros Eugene,
Wang Xiaomei,
Kong Yi,
Zhao Huifen,
Weiss David,
Rivella Stefano,
Weiss Mitchell J.,
Persons Derek A.
Publication year - 2010
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.21829
Subject(s) - thalassemia , hemoglobin , alpha (finance) , alpha thalassemia , alpha globulin , beta thalassemia , hemoglobinopathy , medicine , biology , hemolytic anemia , genetics , gene , surgery , genotype , construct validity , patient satisfaction
Excess free alpha-globin is cytotoxic and contributes to the pathophysiology of b-thalassemia. Alpha hemoglobin stabilizing protein (AHSP) is a molecular chaperone that binds free alpha-globin to promote its folding and inhibit its ability to produce damaging reactive oxygen species. Reduced AHSP levels correlate with increased severity of b-thalassemia in some human cohorts, but causal mechanistic relationships are not established for these associations. We used transgenic and lentiviral gene transfer methods to investigate whether supraphysiologic AHSP levels could mitigate the severity of b-thalassemia intermedia by providing an increased sink for the excess pool of alpha-globin chains. We tested wild-type AHSP and two mutant versions with amino acid substitutions that confer 3- or 13-fold higher affinity for alpha-globin. Erythroid overexpression of these AHSP proteins up to 11-fold beyond endogenous levels had no major effects on hematologic parameters in b-thalassemic animals. Our results demonstrate that endogenous AHSP is not limiting for a-globin detoxification in a murine model of b-thalassemia.