dc.contributor.author | Kahle, KT | |
dc.contributor.author | Flores, B | |
dc.contributor.author | Zhang, J | |
dc.contributor.author | Bharucha-Goebel, D | |
dc.contributor.author | Donkervoort, S | |
dc.contributor.author | Hegde, M | |
dc.contributor.author | Hussain, G | |
dc.contributor.author | Duran, D | |
dc.contributor.author | Liang, B | |
dc.contributor.author | Sun, D | |
dc.contributor.author | Bönnemann, CG | |
dc.contributor.author | Delpire, E | |
dc.date.accessioned | 2018-07-06T13:58:17Z | |
dc.date.issued | 2016-08-02 | |
dc.description.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 in humans. | en_GB |
dc.description.sponsorship | This work was supported by NIH research grant GM74771 (E.D.). K.T.K. was supported by a Harvard-MIT Neuroscience Grant, the Manton Center for Orphan Disease Research at Harvard Medical School, and the March of Dimes. 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. | en_GB |
dc.identifier.citation | Vol. 9 (439), pp. ra77. | en_GB |
dc.identifier.doi | 10.1126/scisignal.aae0546 | |
dc.identifier.uri | http://hdl.handle.net/10871/33389 | |
dc.language.iso | en | en_GB |
dc.publisher | American Association for the Advancement of Science | en_GB |
dc.relation.source | The KCC3-Thr991Ala mouse is available upon request. | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/27485015 | en_GB |
dc.rights | Copyright © 2016, American Association for the Advancement of Science | en_GB |
dc.subject | Animals | en_GB |
dc.subject | Female | en_GB |
dc.subject | HEK293 Cells | en_GB |
dc.subject | Humans | en_GB |
dc.subject | Male | en_GB |
dc.subject | Mice | en_GB |
dc.subject | Mice, Mutant Strains | en_GB |
dc.subject | Motor Neurons | en_GB |
dc.subject | Mutation, Missense | en_GB |
dc.subject | Peripheral Nervous System Diseases | en_GB |
dc.subject | Phosphorylation | en_GB |
dc.subject | Symporters | en_GB |
dc.subject | WNK Lysine-Deficient Protein Kinase 1 | en_GB |
dc.title | Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-07-06T13:58:17Z | |
dc.identifier.issn | 1945-0877 | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this record. | en_GB |
dc.identifier.journal | Science Signaling | en_GB |