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https://hdl.handle.net/2440/121957
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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 1528-0020 |
Statement of Responsibility: | 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 Humans Mice Mice, Mutant Strains Anemia, Sickle Cell Disease Models, Animal Symporters 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 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/382900 |
Published version: | http://dx.doi.org/10.1182/blood-2014-10-609362 |
Appears in Collections: | Aurora harvest 4 Medical Sciences publications |
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