title: Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy.
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.
authors.affiliation: 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.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: 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.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Merner
authors.affiliation: INMED, INSERM Unité 901, Marseille, France Aix-Marseille Université UMR 901, Marseille, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Friedel
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Liliya
authors.initials: L
authors.lastname: Silayeva
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology (BCMP), Harvard Medical School, Boston, MA, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Khanna
authors.affiliation: 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.
authors.forename: Yuze
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Center of Research of the Université de Montréal and the Department of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Pamela
authors.initials: P
authors.lastname: Lachance-Touchette
authors.affiliation: Center of Research of the Université de Montréal and the Department of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bourassa
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Levert
authors.affiliation: 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.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Walcott
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.affiliation: CHU Sainte Justine Research Centre, Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Hodgkinson
authors.affiliation: CHU Sainte Justine Research Centre, Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada CARTaGENE, Montréal, QC, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada.
authors.forename: Hamid
authors.initials: H
authors.lastname: Nikbakht
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Center of Research of the Université de Montréal and the Department of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Tarek Z
authors.initials: TZ
authors.lastname: Deeb
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: INMED, INSERM Unité 901, Marseille, France Aix-Marseille Université UMR 901, Marseille, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Medina
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute McGill Université, Montréal, QC, Canada guy.rouleau@mcgill.ca.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000200:Action Potentials; D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000378:metabolism*; D005787:Gene Frequency; D014644:Genetic Variation; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017966:Pyramidal Cells / Q000378:metabolism; D011792:Quebec; D051381:Rats; D027981:Symporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: GABA; KCC2; cation‐chloride cotransporters; epilepsy; kinase