Auteurs
Kahle KT - Merner ND - Friedel P - Silayeva L - Liang B - Khanna A - Shang Y - Lachance-Touchette P - Bourassa C - Levert A - Dion PA - Walcott B - Spiegelman D - Dionne-Laporte A - Hodgkinson A - Awadalla P - Nikbakht H - Majewski J - Cossette P - Deeb TZ - Moss SJ - Medina I - Rouleau GA
Journal
EMBO reports
Abstract
The KCC2 cotransporter establishes the low neuronal Cl(-) levels required for GABAA and glycine (Gly) receptor-mediated inhibition, and KCC2 deficiency in model organisms results in network hyperexcitability. However, no mutations in KCC2 have been documented in human disease. Here, we report two non-synonymous functional variants in human KCC2, R952H and R1049C, exhibiting clear statistical association with idiopathic generalized epilepsy (IGE). These variants reside in conserved residues in the KCC2 cytoplasmic C-terminus, exhibit significantly impaired Cl(-)-extrusion capacities resulting in less hyperpolarized Gly equilibrium potentials (EG ly), and impair KCC2 stimulatory phosphorylation at serine 940, a key regulatory site. These data describe a novel KCC2 variant significantly associated with a human disease and suggest genetically encoded impairment of KCC2 functional regulation may be a risk factor for the development of human IGE.