Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model
- Author(s)
- Brown, FC; Conway, AJ; Cerruti, L; Collinge, JE; McLean, C; WILEY, JS; Kile, BT; Jane, SM; Curtis, DJ;
- Details
- Publication Year 2015-12-24,Volume 126,Issue #26,Page 2863-70
- Journal Title
- Blood
- Publication Type
- Journal Article
- 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.
- Publisher
- ASH
- Research Division(s)
- Chemical Biology
- PubMed ID
- 26450986
- Publisher's Version
- https://doi.org/10.1182/blood-2014-10-609362
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-02-17 04:20:08
Last Modified: 2016-02-17 04:22:23