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.

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
  • 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
  • potassium-chloride symporters