RESUMO
Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
Assuntos
Epilepsia/genética , Mutação , Convulsões Febris/genética , Sintaxina 1/genética , Sequência de Aminoácidos , Animais , Códon sem Sentido , Estudos de Coortes , Hibridização Genômica Comparativa , Exoma , Feminino , Deleção de Genes , Ligação Genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Temperatura , Peixe-ZebraRESUMO
Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels. Recently, mutations in the gene coding for the skeletal muscle voltage-gated sodium channel alpha subunit (SCN4A) have been reported. We detected the R672H mutation in one HypoPP Turkish family.
