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

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.
Martin Puskarjov 1,  Patricia Seja 1,  Sarah E Heron 2,  Tristiana C Williams 3,  Faraz Ahmad 1,  Xenia Iona 3,  Karen L Oliver 4,  Bronwyn E Grinton 5,  Laszlo Vutskits 6,  Ingrid E Scheffer 7,  Steven Petrou 8,  Peter Blaesse 9,  Leanne M Dibbens 2,  Samuel F Berkovic 4,  Kai Kaila 10
Affiliations

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 [email protected].
PMID: 24668262 DOI: 10.1002/embr.201438749
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.

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