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

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.

SUBMITTER: Puskarjov M

PROVIDER: S-EPMC4197883 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Puskarjov Martin M Seja Patricia P Heron Sarah E SE Williams Tristiana C TC Ahmad Faraz F Ahmad Faraz F Iona Xenia X Oliver Karen L KL Grinton Bronwyn E BE Vutskits Laszlo L Scheffer Ingrid E IE Petrou Steven S Blaesse Peter P Dibbens Leanne M LM Berkovic Samuel F SF Kaila Kai K

EMBO reports 20140324 6

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. Biochemi ...[more]

PMID: 24668262

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