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Sci Signal. 2016 Aug 2;9(439):ra77. doi: 10.1126/scisignal.aae0546.

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

Author information

1
Departments of Neurosurgery and Pediatrics and Cellular and Molecular Physiology, Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA.
2
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3
Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20814, USA. Department of Neurology, Children's National Health System, Washington, DC 20010, USA.
4
Departments of Neurosurgery and Pediatrics and Cellular and Molecular Physiology, Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA. MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
5
Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20814, USA.
6
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
7
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center Pittsburgh, PA 15240, USA.
8
Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02114, USA.
9
Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20814, USA. eric.delpire@vanderbilt.edu carsten.bonnemann@nih.gov.
10
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. eric.delpire@vanderbilt.edu carsten.bonnemann@nih.gov.

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.

PMID:
27485015
PMCID:
PMC5506493
DOI:
10.1126/scisignal.aae0546
[Indexed for MEDLINE]
Free PMC Article

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