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
  • 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.