title: Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.
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.
authors.affiliation: Departments of Neurosurgery and Pediatrics and Cellular and Molecular Physiology, Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Bianca
authors.initials: B
authors.lastname: Flores
authors.affiliation: 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.
authors.forename: Diana
authors.initials: D
authors.lastname: Bharucha-Goebel
authors.affiliation: 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.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20814, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Hegde
authors.affiliation: 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.
authors.forename: Gulnaz
authors.initials: G
authors.lastname: Hussain
authors.affiliation: Departments of Neurosurgery and Pediatrics and Cellular and Molecular Physiology, Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Duran
authors.affiliation: Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. eric.delpire@vanderbilt.edu carsten.bonnemann@nih.gov.
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
mesh_terms: D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D020125:Mutation, Missense; D010523:Peripheral Nervous System Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D027981:Symporters; D000076204:WNK Lysine-Deficient Protein Kinase 1; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters; C492280:Slc12a6 protein, mouse; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse