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Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy |
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| Authors: | 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 |
| Institution: | 1. Department of Cardiology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, , Boston, MA, USA;2. Department of Neurosurgery, Massachusetts General Hospital, , Boston, MA, USA;3. Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, , Auburn, AL, USA;4. Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill Université, , Montréal, QC, Canada;5. INMED, INSERM Unité 901, , Marseille, France;6. Aix‐Marseille Université, UMR 901, , Marseille, France;7. Department of Neuroscience, Tufts University School of Medicine, , Boston, MA, USA;8. Department of Biological Chemistry and Molecular Pharmacology (BCMP), Harvard Medical School, , Boston, MA, USA;9. Center of Research of the Université de Montréal and the Department of Medicine, Université de Montréal, , Montréal, QC, Canada;10. Department of Pathology and Cell Biology, Université de Montréal, , Montréal, QC, Canada;11. CHU Sainte Justine Research Centre, Department of Pediatrics, Faculty of Medicine, Université de Montréal, , Montréal, QC, Canada;12. CARTaGENE, , Montréal, QC, Canada;13. Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, , Montréal, QC, Canada |
| 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. |
| Keywords: | cation‐chloride cotransporters epilepsy GABA KCC2 kinase |