TY - JOUR
T1 - Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter
AU - Kahle, Kristopher T.
AU - Flores, Bianca
AU - Bharucha-Goebel, Diana
AU - Zhang, Jinwei
AU - Donkervoort, Sandra
AU - Hegde, Madhuri
AU - Hussain, Gulnaz
AU - Duran, Daniel
AU - Liang, Bo
AU - Sun, Dandan
AU - Bönnemann, Carsten G.
AU - Delpire, Eric
N1 - This work was supported by NIH research grant GM74771 (E.D.). K.T.K. was supported by a Harvard–Massachusetts Institute of Technology Neuroscience Grant, the Manton Center for Orphan Disease Research at Harvard Medical School, and the March of Dimes Basil O’Connor Award. 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.
PY - 2016/8/2
Y1 - 2016/8/2
N2 - 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.
AB - 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.
U2 - 10.1126/scisignal.aae0546
DO - 10.1126/scisignal.aae0546
M3 - Article
C2 - 27485015
SN - 1937-9145
VL - 9
SP - 1
EP - 15
JO - Science Signaling
JF - Science Signaling
IS - 439
M1 - ra77
ER -