Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter

• Type of Material: Article
• Authors: Kristopher T. Kahle, Yale School of Medicine; Bianca Flores, Vanderbilt University; Diana Bharucha-Goebel, NINDS; Jinwei Zhang, Yale Sch Med; Sandra Donkervoort, National Institute of Neurological Disorders and Stroke; Madhuri Hegde, Emory University; Gulnaz Begum, University of Pittsburgh; Daniel Duran, Yale School of Medicine; Bo Liang, Harvard Medical School; Dandan Sun, University of Pittsburgh; Carsten G. Bonnemann, National Institute of Neurological Disorders and Stroke; Eric Delpire, Vanderbilt University
• Language: English
• Date: 2016-08-02
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Association for the Advancement of Science. All rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/scisignal.aae0546
• Title of Journal or Parent Work: Science Signaling
• ISSN: 1945-0877
• Volume: 9
• Issue: 439
• Start Page: ra77
• End Page: ra77
• Grant/Funding Information: C.G.B. is supported by intramural funds of the NINDS. B.F. and D.B.G. received support from NIH grants 2T32MH064913-11A1 and T32-AR056993, respectively.; K.T.K. was supported by a Harvard–Massachusetts Institute of Technology Neuroscience Grant, the Manton Center for Orphan Disease Research at Harvard Medical School, and the March of Dimes Basil O'Connor Award.; This work was supported by NIH research grant GM74771 (E.D.).
• Keywords: CELL-VOLUME HOMEOSTASIS; Biochemistry & Molecular Biology; MISSENSE MUTATIONS; Cell Biology; HEREDITARY MOTOR; MICE; K+-CL-COTRANSPORTER; CATION-CHLORIDE COTRANSPORTERS; ANDERMANN-SYNDROME; DISEASE; Life Sciences & Biomedicine; Science & Technology; CORPUS-CALLOSUM; CONDITIONAL MOUSE MODEL
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

Using exome sequencing, we identified a de novo mutation (c.2971A > G; T991A) in SLC12A6, the gene encoding the K + -Cl - cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons. Normally, the WNK kinase-dependent phosphorylation of T 991 tonically inhibits KCC3; however, cell swelling triggers Thr 991 dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr 991 phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3 T991A/T991A mutant mice exhibited constitutive KCC3 activity and recapitulated aspects of the clinical, electrophysiological, and histopathological findings of the patient. These results suggest that the function of the peripheral nervous system depends on finely tuned, kinase-regulated KCC3 activity and implicate abnormal cell volume homeostasis as a previously unreported mechanism of axonal degeneration.