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Author Notes:

Corresponding author. eric.delpire@vanderbilt.edu (E.D.); carsten.bonnemann@nih.gov (C.G.B.)

See publication for full list of author contributions.

We thank J. Skelton and L. Gower (Vanderbilt Transgenic Mouse/Embryonic Stem Cell Shared Resource) for their expertise in the injection and manipulation of mouse embryos.

We also thank N. Byun (Department of Pharmacology, Vanderbilt University Medical Center) and A. Peltier (Department of Neurology, Vanderbilt University Medical Center) for their help in training and data analyses of nerve conduction experiments.

We also thank D. R. Alessi (University of Dundee) for his support with the reagents and resources.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

This work was supported by NIH research grant GM74771 (E.D.).

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.

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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • CATION-CHLORIDE COTRANSPORTERS
  • CONDITIONAL MOUSE MODEL
  • CELL-VOLUME HOMEOSTASIS
  • K+-CL-COTRANSPORTER
  • CORPUS-CALLOSUM
  • MISSENSE MUTATIONS
  • ANDERMANN-SYNDROME
  • HEREDITARY MOTOR
  • DISEASE
  • MICE

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

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Journal Title:

Science Signaling

Volume:

Volume 9, Number 439

Publisher:

, Pages ra77-ra77

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 American Association for the Advancement of Science. All rights Reserved.

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