A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

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

doi:10.1002/embr.201438749

A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

EMBO Rep. 2014 Jun;15(6):723-9. doi: 10.1002/embr.201438749. Epub 2014 Mar 24.

Authors

Affiliations

¹ Department of Biosciences, University of Helsinki, Helsinki, Finland Neuroscience Center, University of Helsinki, Helsinki, Finland.
² 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.
³ Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
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 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.
⁸ Florey Institute of Neuroscience and Mental Health and the Center for Neural Engineering, The University of Melbourne, Parkville, Vic., Australia.
⁹ Department of Biosciences, University of Helsinki, Helsinki, Finland Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
¹⁰ Department of Biosciences, University of Helsinki, Helsinki, Finland Neuroscience Center, University of Helsinki, Helsinki, Finland Kai.Kaila@Helsinki.fi.

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: KCC2; dendritic spines; febrile seizures; genic intolerance; mutation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Australia
Blotting, Western
Chlorides / metabolism
Dendritic Spines / genetics
Dendritic Spines / pathology*
Genetic Predisposition to Disease / genetics*
Humans
K Cl- Cotransporters
Mice
Mice, Inbred ICR
Microscopy, Fluorescence
Models, Molecular*
Molecular Sequence Data
Mutation, Missense / genetics*
Neurons / metabolism*
Pedigree
Protein Conformation
Rats
Rats, Wistar
Seizures, Febrile / genetics*
Statistics, Nonparametric
Symporters / genetics*
Symporters / metabolism

Substances

Chlorides
Symporters