Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy.
EMBO Rep
; 15(7): 766-74, 2014 Jul.
Article
in En
| MEDLINE
| ID: mdl-24928908
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Epilepsy, Generalized
/
Symporters
Type of study:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Country/Region as subject:
America do norte
Language:
En
Journal:
EMBO Rep
Journal subject:
BIOLOGIA MOLECULAR
Year:
2014
Type:
Article
Affiliation country:
United States