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Type: Journal article
Title: Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model
Author: Brown, F.C.
Conway, A.J.
Cerruti, L.
Collinge, J.E.
McLean, C.
Wiley, J.S.
Kile, B.T.
Jane, S.M.
Curtis, D.J.
Citation: Blood, 2015; 126(26):2863-2870
Publisher: American Society of Hematology
Issue Date: 2015
ISSN: 0006-4971
Statement of
Fiona C. Brown, Ashlee J. Conway, Loretta Cerruti, Janelle E. Collinge, Catriona McLean, James S. Wiley, Ben T. Kile, Stephen M. Jane, David J. Curtis
Abstract: We used an N-ethyl-N-nitrosurea-based forward genetic screen in mice to identify new genes and alleles that regulate erythropoiesis. Here, we describe a mouse line expressing an activated form of the K-Cl cotransporter Slc12a4 (Kcc1), which results in a semi-dominant microcytosis of red cells. A missense mutation from methionine to lysine in the cytoplasmic tail of Kcc1 impairs phosphorylation of adjacent threonines required for inhibiting cotransporter activity. We bred Kcc1(M935K) mutant mice with a humanized mouse model of sickle cell disease to directly explore the relevance of the reported increase in KCC activity in disease pathogenesis. We show that a single mutant allele of Kcc1 induces widespread sickling and tissue damage, leading to premature death. This mouse model reveals important new insights into the regulation of K-Cl cotransporters and provides in vivo evidence that increased KCC activity worsened end-organ damage and diminished survival in sickle cell disease.
Keywords: Animals
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Mutant Strains
Anemia, Sickle Cell
Disease Models, Animal
Reverse Transcriptase Polymerase Chain Reaction
Mutation, Missense
High-Throughput Nucleotide Sequencing
Rights: © 2015 by The American Society of Hematology
DOI: 10.1182/blood-2014-10-609362
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Appears in Collections:Aurora harvest 4
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