Schubert, J.2; Siekierska, A.2; Langlois, M.2; May, P.2; Huneau, C.2; Becker, F.2; Muhle, H.2; Suls, A.2; Lemke, J. R.2; de Kovel, C. G. F.2; Thiele, H.2; Konrad, K.2; Kawalia, A.2; Toliat, M. R.2; Sander, T.2; Ruschendorf, F.2; Caliebe, A.2; Nagel, I.2; Kohl, B.2; Kecskes, A.2; Jacmin, M.2; Hardies, K.2; Weckhuysen, S.2; Riesch, E.2; Dorn, T.2; Brilstra, E. H.2; Baulac, S.2; Moller, R. S.3; Hjalgrim, H.3; Koeleman, B. P. C.2; Jurkat-Rott, K.2; Lehman-Horn, F.2; Roach, J. C.2; Glusman, G.2; Hood, L.2; Galas, D. J.2; Martin, B.2; de Witte, P. A. M.2; Biskup, S.2; De Jonghe, P.2; Helbig, I.2; Balling, R.2; Nurnberg, P.2; Crawford, A. D.2; Esguerra, C. V.2; Weber, Y. G.2; Lerche, H.2; Euro, Epinomics R. E. S. Consortium2
1 Danish Epilepsy Centre, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU2 unknown3 Danish Epilepsy Centre, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU
Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B(6), that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees(7,8) 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.
Nature Genetics, 2014, Vol 46, Issue 12, p. 1327-1332