Loss of $\alpha$-hemoglobin–stabilizing protein impairs erythropoiesis and exacerbates $\beta$-thalassemia. Kong, Y.; Zhou, S.; Kihm, A. J.; Katein, A. M.; Yu, X.; Gell, D. A.; Mackay, J. P.; Adachi, K.; Foster-Brown, L.; Louden, C. S.; Gow, A. J.; and Weiss, M. J. Journal of Clinical Investigation, 114(10):1457–1466, nov, 2004.
Loss of $\alpha$-hemoglobin–stabilizing protein impairs erythropoiesis and exacerbates $\beta$-thalassemia [link]Paper  doi  abstract   bibtex   
Hemoglobin (Hb) A production during red blood cell development is coordinated to minimize the deleterious effects of free alpha- and beta-Hb subunits, which are unstable and cytotoxic. The alpha-Hb-stabilizing protein (AHSP) is an erythroid protein that specifically binds alpha-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free alpha-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 alpha-Hb, AHSP(-/-) erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by alpha-Hb in solution. Finally, loss of AHSP worsened the phenotype of beta-thalassemia, a common inherited anemia characterized by excess free alpha-Hb. Together, the data support a model in which AHSP binds alpha-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 beta-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of beta-thalassemia in humans.
@article{Kong2004,
abstract = {Hemoglobin (Hb) A production during red blood cell development is coordinated to minimize the deleterious effects of free alpha- and beta-Hb subunits, which are unstable and cytotoxic. The alpha-Hb-stabilizing protein (AHSP) is an erythroid protein that specifically binds alpha-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free alpha-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 alpha-Hb, AHSP(-/-) erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by alpha-Hb in solution. Finally, loss of AHSP worsened the phenotype of beta-thalassemia, a common inherited anemia characterized by excess free alpha-Hb. Together, the data support a model in which AHSP binds alpha-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 beta-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of beta-thalassemia in humans.},
annote = {cited By 110},
author = {Kong, Yi and Zhou, Suiping and Kihm, Anthony J. and Katein, Anne M. and Yu, Xiang and Gell, David A. and Mackay, Joel P. and Adachi, Kazuhiko and Foster-Brown, Linda and Louden, Calvert S. and Gow, Andrew J. and Weiss, Mitchell J.},
doi = {10.1172/JCI21982},
issn = {0021-9738},
journal = {Journal of Clinical Investigation},
month = {nov},
number = {10},
pages = {1457--1466},
pmid = {15545996},
title = {{Loss of $\alpha$-hemoglobin–stabilizing protein impairs erythropoiesis and exacerbates $\beta$-thalassemia}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15545996},
volume = {114},
year = {2004}
}
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