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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Alleles
  • Animals
  • Case-Control Studies
  • Cell Line
  • Chlorides / metabolism
  • Epilepsy, Generalized / genetics*
  • Epilepsy, Generalized / metabolism*
  • Gene Frequency
  • Genetic Variation
  • Hippocampus / metabolism
  • Humans
  • Models, Molecular
  • Mutation
  • Phosphorylation
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Pyramidal Cells / metabolism
  • Quebec
  • Rats
  • Symporters / chemistry
  • Symporters / genetics*
  • Symporters / metabolism*


  • Chlorides
  • Symporters
  • potassium-chloride symporters

Supplementary concepts

  • Epilepsy, Idiopathic Generalized