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A variant of KCC2 from patients with febrile seizures impairs neuronal Cl− extrusion and dendritic spine formation |
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| Authors: | Martin Puskarjov Patricia Seja Sarah E Heron Tristiana C Williams Faraz Ahmad Xenia Iona Karen L Oliver Bronwyn E Grinton Laszlo Vutskits Ingrid E Scheffer Steven Petrou Peter Blaesse Leanne M Dibbens Samuel F Berkovic Kai Kaila |
| Affiliation: | 1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia;2. Department of Biosciences, University of Helsinki, Helsinki, Finland;3. Neuroscience Center, University of Helsinki, Helsinki, Finland;4. Department of Medicine, Epilepsy Research Center, The University of Melbourne, Austin Health, Melbourne, Vic., Australia;5. Department of Paediatrics, Florey Institute, Royal Children's Hospital, The University of Melbourne, Melbourne, Vic., Australia;6. Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland;7. Florey Institute of Neuroscience and Mental Health and the Center for Neural Engineering, The University of Melbourne, Parkville, Vic., Australia;8. Institute of Physiology I, Westf?lische Wilhelms‐University Münster, Münster, Germany;9. Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia |
| 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. |
| Keywords: | dendritic spines febrile seizures genic intolerance KCC2 mutation |