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

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

Author information

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

PMID:
24668262
PMCID:
PMC4197883
DOI:
10.1002/embr.201438749
[Indexed for MEDLINE]
Free PMC Article

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