Puskarjov Martin, Seja Patricia, Heron Sarah E, Williams Tristiana C, Ahmad Faraz, Iona Xenia, Oliver Karen L, Grinton Bronwyn E, Vutskits Laszlo, Scheffer Ingrid E, Petrou Steven, Blaesse Peter, Dibbens Leanne M, Berkovic Samuel F, Kaila Kai
Department of Biosciences, University of Helsinki, Helsinki, Finland Neuroscience Center, University of Helsinki, Helsinki, Finland.
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.
EMBO Rep. 2014 Jun;15(6):723-9. doi: 10.1002/embr.201438749. Epub 2014 Mar 24.
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.
编码KCC2的SLC12A5基因发生变异，KCC2是神经元特异性阳离子-氯离子协同转运蛋白，对超极化GABA能信号传导和皮质树突棘的形成至关重要，此前尚未在人类疾病中报道过该基因变异。对SLC12A5进行筛查时，在一个患有热性惊厥的澳大利亚家族中发现了一个共分离变异（KCC2-R952H）。我们发现，KCC2-R952H会降低神经元对Cl(-)的外排能力，并且在体内和体外诱导树突棘形成方面的能力受损。生化分析表明，KCC2-R952H的表面表达减少，这可能导致了功能缺陷。我们的数据表明，KCC2-R952H是热性惊厥的一个真正的易感变异。
