Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Julian Schubert; Aleksandra Siekierska; Melanie Langlois; Patrick May; Clement Huneau; Felicitas Becker; Hiltrud Muhle; Arvid Suls; Johannes R. Lemke; Carolien G F  de Kovel; Holger Thiele; Kathryn Konrad; Amit Kawalia; Mohammad R. Toliat; Thomas Sander; Franz Rueschendorf; Almuth Caliebe; Inga Nagel; Bernard Kohl; Angela Kecskes; Maxime Jacmin; Katia Hardies; Sarah Weckhuysen; Erik Riesch; Thomas Dorn; Eva H. Brilstra; Stephanie Baulac; Rikke S. Moller; Helle Hjalgrim; Bobby P. C.  Koeleman; Karin Jurkat-Rott; Frank Lehman-Horn; Jared C. Roach; Gustavo Glusman; Leroy Hood; David J. Galas; Benoit Martin; Peter A. M. de Witte; Saskia Biskup; Peter De Jonghe; Ingo Helbig; Rudi Balling; Peter Nuernberg; Alexander D. Crawford; Camila V. Esguerra; Yvonne G. Weber; Holger Lerche; BPC Koeleman

doi:10.1038/ng.3130

Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Julian Schubert, Aleksandra Siekierska, Melanie Langlois, Patrick May, Clement Huneau, Felicitas Becker, Hiltrud Muhle, Arvid Suls, Johannes R. Lemke, Carolien G F de Kovel, Holger Thiele, Kathryn Konrad, Amit Kawalia, Mohammad R. Toliat, Thomas Sander, Franz Rueschendorf, Almuth Caliebe, Inga Nagel, Bernard Kohl, Angela KecskesMaxime Jacmin, Katia Hardies, Sarah Weckhuysen, Erik Riesch, Thomas Dorn, Eva H. Brilstra, Stephanie Baulac, Rikke S. Moller, Helle Hjalgrim, Bobby P. C. Koeleman, Karin Jurkat-Rott, Frank Lehman-Horn, Jared C. Roach, Gustavo Glusman, Leroy Hood, David J. Galas, Benoit Martin, Peter A. M. de Witte, Saskia Biskup, Peter De Jonghe, Ingo Helbig, Rudi Balling, Peter Nuernberg, Alexander D. Crawford, Camila V. Esguerra, Yvonne G. Weber, Holger Lerche^*, , BPC Koeleman

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1327-1332
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	12
DOIs	https://doi.org/10.1038/ng.3130
Publication status	Published - Dec 2014

Keywords

PAROXYSMAL KINESIGENIC DYSKINESIA
SYNAPTIC VESICLE FUSION
DE-NOVO MUTATIONS
FEBRILE SEIZURES
INFANTILE CONVULSIONS
GENERALIZED EPILEPSY
PRRT2 MUTATIONS
GENERATION
DISORDERS
ZEBRAFISH

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Schubert, J., Siekierska, A., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., de Kovel, C. G. F., Thiele, H., Konrad, K., Kawalia, A., Toliat, M. R., Sander, T., Rueschendorf, F., Caliebe, A., Nagel, I., Kohl, B., ... Koeleman, BPC. (2014). Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nature Genetics, 46(12), 1327-1332. https://doi.org/10.1038/ng.3130

@article{7819033cc5f3432187872b6151bf9c9a,

title = "Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes",

abstract = "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.",

keywords = "PAROXYSMAL KINESIGENIC DYSKINESIA, SYNAPTIC VESICLE FUSION, DE-NOVO MUTATIONS, FEBRILE SEIZURES, INFANTILE CONVULSIONS, GENERALIZED EPILEPSY, PRRT2 MUTATIONS, GENERATION, DISORDERS, ZEBRAFISH",

author = "Julian Schubert and Aleksandra Siekierska and Melanie Langlois and Patrick May and Clement Huneau and Felicitas Becker and Hiltrud Muhle and Arvid Suls and Lemke, {Johannes R.} and {de Kovel}, {Carolien G F} and Holger Thiele and Kathryn Konrad and Amit Kawalia and Toliat, {Mohammad R.} and Thomas Sander and Franz Rueschendorf and Almuth Caliebe and Inga Nagel and Bernard Kohl and Angela Kecskes and Maxime Jacmin and Katia Hardies and Sarah Weckhuysen and Erik Riesch and Thomas Dorn and Brilstra, {Eva H.} and Stephanie Baulac and Moller, {Rikke S.} and Helle Hjalgrim and Koeleman, {Bobby P. C.} and Karin Jurkat-Rott and Frank Lehman-Horn and Roach, {Jared C.} and Gustavo Glusman and Leroy Hood and Galas, {David J.} and Benoit Martin and {de Witte}, {Peter A. M.} and Saskia Biskup and {De Jonghe}, Peter and Ingo Helbig and Rudi Balling and Peter Nuernberg and Crawford, {Alexander D.} and Esguerra, {Camila V.} and Weber, {Yvonne G.} and Holger Lerche and BPC Koeleman",

year = "2014",

month = dec,

doi = "10.1038/ng.3130",

language = "English",

volume = "46",

pages = "1327--1332",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Schubert, J, Siekierska, A, Langlois, M, May, P, Huneau, C, Becker, F, Muhle, H, Suls, A, Lemke, JR, de Kovel, CGF, Thiele, H, Konrad, K, Kawalia, A, Toliat, MR, Sander, T, Rueschendorf, F, Caliebe, A, Nagel, I, Kohl, B, Kecskes, A, Jacmin, M, Hardies, K, Weckhuysen, S, Riesch, E, Dorn, T, Brilstra, EH, Baulac, S, Moller, RS, Hjalgrim, H, Koeleman, BPC, Jurkat-Rott, K, Lehman-Horn, F, Roach, JC, Glusman, G, Hood, L, Galas, DJ, Martin, B, de Witte, PAM, Biskup, S, De Jonghe, P, Helbig, I, Balling, R, Nuernberg, P, Crawford, AD, Esguerra, CV, Weber, YG, Lerche, H & Koeleman, BPC 2014, 'Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes', Nature Genetics, vol. 46, no. 12, pp. 1327-1332. https://doi.org/10.1038/ng.3130

TY - JOUR

T1 - Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

AU - Schubert, Julian

AU - Siekierska, Aleksandra

AU - Langlois, Melanie

AU - May, Patrick

AU - Huneau, Clement

AU - Becker, Felicitas

AU - Muhle, Hiltrud

AU - Suls, Arvid

AU - Lemke, Johannes R.

AU - de Kovel, Carolien G F

AU - Thiele, Holger

AU - Konrad, Kathryn

AU - Kawalia, Amit

AU - Toliat, Mohammad R.

AU - Sander, Thomas

AU - Rueschendorf, Franz

AU - Caliebe, Almuth

AU - Nagel, Inga

AU - Kohl, Bernard

AU - Kecskes, Angela

AU - Jacmin, Maxime

AU - Hardies, Katia

AU - Weckhuysen, Sarah

AU - Riesch, Erik

AU - Dorn, Thomas

AU - Brilstra, Eva H.

AU - Baulac, Stephanie

AU - Moller, Rikke S.

AU - Hjalgrim, Helle

AU - Koeleman, Bobby P. C.

AU - Jurkat-Rott, Karin

AU - Lehman-Horn, Frank

AU - Roach, Jared C.

AU - Glusman, Gustavo

AU - Hood, Leroy

AU - Galas, David J.

AU - Martin, Benoit

AU - de Witte, Peter A. M.

AU - Biskup, Saskia

AU - De Jonghe, Peter

AU - Helbig, Ingo

AU - Balling, Rudi

AU - Nuernberg, Peter

AU - Crawford, Alexander D.

AU - Esguerra, Camila V.

AU - Weber, Yvonne G.

AU - Lerche, Holger

AU - Koeleman, BPC

PY - 2014/12

Y1 - 2014/12

N2 - 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.

AB - 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.

KW - PAROXYSMAL KINESIGENIC DYSKINESIA

KW - SYNAPTIC VESICLE FUSION

KW - DE-NOVO MUTATIONS

KW - FEBRILE SEIZURES

KW - INFANTILE CONVULSIONS

KW - GENERALIZED EPILEPSY

KW - PRRT2 MUTATIONS

KW - GENERATION

KW - DISORDERS

KW - ZEBRAFISH

U2 - 10.1038/ng.3130

DO - 10.1038/ng.3130

M3 - Article

SN - 1061-4036

VL - 46

SP - 1327

EP - 1332

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Abstract

Keywords

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