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.
Kristopher T Kahle  1 ,  Nancy D Merner  2 ,  Perrine Friedel  3 ,  Liliya Silayeva  4 ,  Bo Liang  5 ,  Arjun Khanna  6 ,  Yuze Shang  1 ,  Pamela Lachance-Touchette  7 ,  Cynthia Bourassa  7 ,  Annie Levert  8 ,  Patrick A Dion  9 ,  Brian Walcott  6 ,  Dan Spiegelman  8 ,  Alexandre Dionne-Laporte  8 ,  Alan Hodgkinson  10 ,  Philip Awadalla  11 ,  Hamid Nikbakht  12 ,  Jacek Majewski  12 ,  Patrick Cossette  7 ,  Tarek Z Deeb  4 ,  Stephen J Moss  4 ,  Igor Medina  3 ,  Guy A Rouleau  13
Affiliations
  • 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 [email protected].
PMID: 24928908 DOI: 10.15252/embr.201438840
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.