Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model

Fiona C Brown, Ashlee J Conway, Loretta Cerruti, Janelle E Collinge, Catriona McLean, James S Wiley, Ben T Kile, Stephen M Jane, David John Curtis

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

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 semidominant 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 Kcc1M935K 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.
Original languageEnglish
Pages (from-to)2863-2870
Number of pages8
JournalBlood
Volume126
Issue number26
DOIs
Publication statusPublished - 2015

Cite this