eCite Digital Repository

Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia


Kong, Y and Zhou, S and Kihm, AJ and Katein, AM and Yu, X and Gell, DA and Mackay, JP and Adachi, K and Foster-Brown, L and Louden, CS and Gow, AJ and Weiss, MJ, Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia, Journal of Clinical Investigation, 114, (10) pp. 1457-1466. ISSN 0021-9738 (2004) [Refereed Article]

DOI: doi:10.1172/JCI200421982


Hemoglobin (Hb) A production during red blood cell development is coordinated to minimize the deleterious effects of free α- and β-Hb subunits, which are unstable and cytotoxic. The α-Hb-stabilizing protein (AHSP) is an erythroid protein that specifically binds α-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free α-Hb toxicities in vivo. We investigated this possibility through gene ablation and biochemical studies. AHSP-/- erythrocytes contained hemoglobin precipitates and were short-lived. In hematopoietic tissues, erythroid precursors were elevated in number but exhibited increased apoptosis. Consistent with unstable α-Hb, AHSP-/- erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by α-Hb in solution. Finally, loss of AHSP worsened the phenotype of β-thalassemia, a common inherited anemia characterized by excess free α-Hb. Together, the data support a model in which AHSP binds α-Hb transiently to stabilize its conformation and render it biochemically inert prior to Hb A assembly. This function is essential for normal erythropoiesis and, to a greater extent, in β-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of β-thalassemia in humans.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Structural biology (incl. macromolecular modelling)
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Gell, DA (Dr David Gell)
ID Code:64545
Year Published:2004
Web of Science® Times Cited:118
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-08-12
Last Modified:2011-08-01

Repository Staff Only: item control page