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

Kahle KT, Flores B, Bharucha-Goebel D, Zhang J, Donkervoort S, Hegde M, Hussain G, Duran D, Liang B, Sun D, Bönnemann CG, Delpire E
Sci Signal. 2016 9 (439): ra77

PMID: 27485015 · PMCID: PMC5506493 · DOI:10.1126/scisignal.aae0546

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 © 2016, American Association for the Advancement of Science.

MeSH Terms (13)

Animals Female HEK293 Cells Humans Male Mice Mice, Mutant Strains Motor Neurons Mutation, Missense Peripheral Nervous System Diseases Phosphorylation Symporters WNK Lysine-Deficient Protein Kinase 1

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