Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia. Kong, Y., Zhou, S., Kihm, A., Katein, A., Yu, X., Gell, D., Mackay, J., Adachi, K., Foster-Brown, L., Louden, C., Gow, A., & Weiss, M. Journal of Clinical Investigation, 114(10):1457-1466, 2004.
doi  abstract   bibtex   
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.
@article{
 title = {Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia},
 type = {article},
 year = {2004},
 pages = {1457-1466},
 volume = {114},
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 last_modified = {2023-01-10T01:46:10.944Z},
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 abstract = {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.},
 bibtype = {article},
 author = {Kong, Y. and Zhou, S. and Kihm, A.J. and Katein, A.M. and Yu, X. and Gell, D.A. and Mackay, J.P. and Adachi, K. and Foster-Brown, L. and Louden, C.S. and Gow, A.J. and Weiss, M.J.},
 doi = {10.1172/JCI21982},
 journal = {Journal of Clinical Investigation},
 number = {10}
}

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