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

Kristopher T Kahle, Nancy D Merner, Perrine Friedel, Liliya Silayeva, Bo Liang, Arjun Khanna, Yuze Shang, Pamela Lachance‐Touchette, Cynthia Bourassa, Annie Levert, Patrick A Dion, Brian Walcott, Dan Spiegelman, Alexandre Dionne‐Laporte, Alan Hodgkinson, Philip Awadalla, Hamid Nikbakht, Jacek Majewski, Patrick Cossette, Tarek Z Deeb, Stephen J Moss, Igor Medina, Guy A Rouleau

Author Affiliations

  1. Kristopher T Kahle1,2,,
  2. Nancy D Merner3,4,,
  3. Perrine Friedel5,6,
  4. Liliya Silayeva7,
  5. Bo Liang8,
  6. Arjun Khanna2,
  7. Yuze Shang1,2,
  8. Pamela Lachance‐Touchette9,
  9. Cynthia Bourassa9,
  10. Annie Levert4,
  11. Patrick A Dion3,10,
  12. Brian Walcott2,
  13. Dan Spiegelman4,
  14. Alexandre Dionne‐Laporte4,
  15. Alan Hodgkinson11,
  16. Philip Awadalla11,12,
  17. Hamid Nikbakht13,
  18. Jacek Majewski13,
  19. Patrick Cossette9,
  20. Tarek Z Deeb7,
  21. Stephen J Moss7,
  22. Igor Medina5,6 and
  23. Guy A Rouleau*,4
  1. 1Department of Cardiology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute Boston Children's Hospital, Boston, MA, USA
  2. 2Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
  3. 3Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
  4. 4Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada
  5. 5INMED, INSERM Unité 901, Marseille, France
  6. 6Aix‐Marseille Université UMR 901, Marseille, France
  7. 7Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
  8. 8Department of Biological Chemistry and Molecular Pharmacology (BCMP), Harvard Medical School, Boston, MA, USA
  9. 9Center of Research of the Université de Montréal and the Department of Medicine, Université de Montréal, Montréal, QC, Canada
  10. 10Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC, Canada
  11. 11CHU Sainte Justine Research Centre, Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
  12. 12CARTaGENE, Montréal, QC, Canada
  13. 13Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada
  1. *Corresponding author. Tel: +1 514 890 8000 ext. 24699; E‐mail: guy.rouleau{at}
  1. These authors contributed equally to this work.

View 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 (EGly), 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.

See also: M Puskarjov et al (June 2014) and

CA Hübner


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Two variants of the neuronal chloride cotransporter KCC2—R952H and R1049C—are found to be associated with human idiopathic generalized epilepsy and to impair transporter function and regulatory phosphorylation. Genetically encoded impairment of KCC2 function may therefore be a risk factor for human epilepsy.

  • Two functional variants in KCC2, R952H and R1049C, are significantly associated with human idiopathic generalized epilepsy (IGE)

  • Compared to WT KCC2, R952H and R1049C exhibit significantly impaired Cl‐extrusion capacities, result in less hyperpolarized glycine equilibrium potentials (EGly), and impair KCC2 serine 940 phosphorylation.

  • Received March 27, 2014.
  • Revision received April 18, 2014.
  • Accepted April 23, 2014.
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