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β-thalassemia (β-Thal) is caused by defective β-globin production leading to globin chain imbalance, aggregation of free alpha chain in developing erythroblasts, reticulocytes, and mature circulating red blood cells. The hypochromic thalassemic red cells exhibit increased cell dehydration in association with elevated K+ leak and increased K-Cl cotransport activity, each of which has been linked to globin chain imbalance and related oxidative stress. We therefore tested the effect of genetic inactivation of K-Cl cotransporters KCC1 and KCC3 in a mouse model of β-thalassemia intermedia. In the absence of these transporters, the anemia of β-Thal mice was ameliorated, in association with increased MCV and reductions in CHCM and hyperdense cells, as well as in spleen size. The resting K+ content of β-Thal red cells was greatly increased, and Thal-associated splenomegaly slightly decreased. Lack of KCC1 and KCC3 activity in Thal red cells reduced red cell density and improved β-Thal-associated osmotic fragility. We conclude that genetic inactivation of K-Cl cotransport can reverse red cell dehydration and partially attenuate the hematologic phenotype in a mouse model of β-thalassemia. Copyright © 2019 Elsevier Inc. All rights reserved.


Boris E Shmukler, Alicia Rivera, Parul Bhargava, Katherine Nishimura, Edward H Kim, Ann Hsu, Jay G Wohlgemuth, James Morton, L Michael Snyder, Lucia De Franceschi, Marco B Rust, Christian A Hubner, Carlo Brugnara, Seth L Alper. Genetic disruption of KCC cotransporters in a mouse model of thalassemia intermedia. Blood cells, molecules & diseases. 2020 Mar;81:102389

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PMID: 31835175

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