RT Journal Article
SR Electronic
T1 Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra77
OP ra77
DO 10.1126/scisignal.aae0546
VO 9
IS 439
A1 Kahle, Kristopher T.
A1 Flores, Bianca
A1 Bharucha-Goebel, Diana
A1 Zhang, Jinwei
A1 Donkervoort, Sandra
A1 Hegde, Madhuri
A1 Begum, Gulnaz
A1 Duran, Daniel
A1 Liang, Bo
A1 Sun, Dandan
A1 Bönnemann, Carsten G.
A1 Delpire, Eric
YR 2016
UL http://stke.sciencemag.org/content/9/439/ra77.abstract
AB Clinical presentation of disease by patients can lead to profoundly important discoveries about basic biology. In this case, a child with progressive, early-onset, motor neuropathy resulting in profound disability revealed a key role for the phosphorylation-mediated regulation of the K+-Cl− transporter KCC3 in the peripheral nervous system. Kahle et al. discovered a point mutation in the gene encoding KCC3 in the patient that prevented the transporter from being inhibited through phosphorylation and resulted in its constitutive activation. Mice expressing KCC3 with the same mutation had increased transporter activity and impaired locomotor function, suggesting that the normal function of peripheral neurons depends on the regulation of KCC3 function.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 T991 tonically inhibits KCC3; however, cell swelling triggers Thr991 dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr991 phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3T991A/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.