title: A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation.
abstract: Genetic variation in SLC12A5 which encodes KCC2, the neuron-specific cation-chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co-segregating variant (KCC2-R952H) in an Australian family with febrile seizures. We show that KCC2-R952H reduces neuronal Cl(-) extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2-R952H which likely contributes to the functional deficits. Our data suggest that KCC2-R952H is a bona fide susceptibility variant for febrile seizures.
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Martin
authors.initials: M
authors.lastname: Puskarjov
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Seja
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia Sansom Institute for Health Research, University of South Australia, Adelaide SA, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Tristiana C
authors.initials: TC
authors.lastname: Williams
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Faraz
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Xenia
authors.initials: X
authors.lastname: Iona
authors.affiliation: Department of Medicine, Epilepsy Research Center, The University of Melbourne Austin Health, Melbourne Vic., Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Oliver
authors.affiliation: Department of Paediatrics, Florey Institute, Royal Children's Hospital The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: Bronwyn E
authors.initials: BE
authors.lastname: Grinton
authors.affiliation: Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Vutskits
authors.affiliation: Department of Medicine, Epilepsy Research Center, The University of Melbourne Austin Health, Melbourne Vic., Australia Department of Paediatrics, Florey Institute, Royal Children's Hospital The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Florey Institute of Neuroscience and Mental Health and the Center for Neural Engineering, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Blaesse
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia Sansom Institute for Health Research, University of South Australia, Adelaide SA, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.affiliation: Department of Medicine, Epilepsy Research Center, The University of Melbourne Austin Health, Melbourne Vic., Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland Neuroscience Center, University of Helsinki, Helsinki, Finland Kai.Kaila@Helsinki.fi.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001315:Australia; D015153:Blotting, Western; D002712:Chlorides / Q000378:metabolism; D049229:Dendritic Spines / Q000235:genetics / Q000473:pathology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D010375:Pedigree; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D003294:Seizures, Febrile / Q000235:genetics*; D018709:Statistics, Nonparametric; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: KCC2; dendritic spines; febrile seizures; genic intolerance; mutation