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EMBO Rep. 2014 Jul;15(7):766-74. doi: 10.15252/embr.201438840. Epub 2014 Jun 13.

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

Author information

1
Department of Cardiology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute Boston Children's Hospital, Boston, MA, USA Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
2
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada.
3
INMED, INSERM Unité 901, Marseille, France Aix-Marseille Université UMR 901, Marseille, France.
4
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
5
Department of Biological Chemistry and Molecular Pharmacology (BCMP), Harvard Medical School, Boston, MA, USA.
6
Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
7
Center of Research of the Université de Montréal and the Department of Medicine, Université de Montréal, Montréal, QC, Canada.
8
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada.
9
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC, Canada.
10
CHU Sainte Justine Research Centre, Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
11
CHU Sainte Justine Research Centre, Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada CARTaGENE, Montréal, QC, Canada.
12
Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada.
13
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada guy.rouleau@mcgill.ca.

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.

KEYWORDS:

GABA; KCC2; cation‐chloride cotransporters; epilepsy; kinase

PMID:
24928908
PMCID:
PMC4196980
DOI:
10.15252/embr.201438840
[Indexed for MEDLINE]
Free PMC Article

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