Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy.
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.
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.