Journal ArticleDOI
SCN1A mutations and epilepsy.
John C. Mulley,Ingrid E. Scheffer,Steven Petrou,Leanne M. Dibbens,Leanne M. Dibbens,Samuel F. Berkovic,Louise A. Harkin,Louise A. Harkin +7 more
TLDR
Of all the known epilepsy genes SCN1A is currently the most clinically relevant, with the largest number of epilepsy related mutations so far characterized, and some clustering of mutations is observed in the C‐terminus and the loops between segments 5 and 6 of the first three domains of the protein.Abstract:
SCN1A is part of the SCN1A-SCN2A-SCN3A gene cluster on chromosome 2q24 that encodes for alpha pore forming subunits of sodium channels. The 26 exons of SCN1A are spread over 100 kb of genomic DNA. Genetic defects in the coding sequence lead to generalized epilepsy with febrile seizures plus (GEFS+) and a range of childhood epileptic encephalopathies of varied severity (e.g., SMEI). All published mutations are collated. More than 100 novel mutations are spread throughout the gene with the more debilitating usually de novo. Some clustering of mutations is observed in the C-terminus and the loops between segments 5 and 6 of the first three domains of the protein. Functional studies so far show no consistent relationship between changes to channel properties and clinical phenotype. Of all the known epilepsy genes SCN1A is currently the most clinically relevant, with the largest number of epilepsy related mutations so far characterized.read more
Citations
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Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations
Brian J. O'Roak,Pelagia Deriziotis,Pelagia Deriziotis,Choli Lee,Laura Vives,Jerrod J. Schwartz,Santhosh Girirajan,Emre Karakoc,Alexandra P. MacKenzie,Sarah B. Ng,Carl Baker,Mark J. Rieder,Deborah A. Nickerson,Raphael Bernier,Simon E. Fisher,Simon E. Fisher,Simon E. Fisher,Jay Shendure,Evan E. Eichler,Evan E. Eichler +19 more
TL;DR: The results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.
Journal ArticleDOI
Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
Frank H. Yu,Massimo Mantegazza,Ruth E. Westenbroek,Carol A. Robbins,Franck Kalume,Kimberly A. Burton,William J. Spain,G. Stanley McKnight,Todd Scheuer,William A. Catterall +9 more
TL;DR: The results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/− heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.
Journal ArticleDOI
Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation
Ikuo Ogiwara,Hiroyuki Miyamoto,Noriyuki Morita,Nafiseh Atapour,Emi Mazaki,Ikuyo Inoue,T. Takeuchi,Shigeyoshi Itohara,Yuchio Yanagawa,Kunihiko Obata,Teiichi Furuichi,Takao K. Hensch,Kazuhiro Yamakawa +12 more
TL;DR: The authors' data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and, furthermore, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice.
Journal ArticleDOI
The spectrum of SCN1A-related infantile epileptic encephalopathies
Louise A. Harkin,Jacinta M McMahon,Xenia Iona,Leanne M. Dibbens,Leanne M. Dibbens,James T. Pelekanos,Sameer M. Zuberi,Lynette G. Sadleir,Eva Andermann,Deepak Gill,Kevin Farrell,Mary B. Connolly,Thorsten Stanley,Michael Harbord,Frederick Andermann,Jing Wang,Sat Dev Batish,Jeffrey G. Jones,William K Seltzer,Alison Gardner,Grant R. Sutherland,Grant R. Sutherland,Samuel F. Berkovic,John C. Mulley,John C. Mulley,Ingrid E. Scheffer,Ingrid E. Scheffer +26 more
TL;DR: Knowing of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders, including cryptogenic generalized epilepsy and cryptogenic focal epilepsy.
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Journal ArticleDOI
SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome
Qing Kenneth Wang,Jiaxiang Shen,Jiaxiang Shen,Igor Splawski,Donald L. Atkinson,Donald L. Atkinson,Zhizhong Li,Jennifer L. Robinson,Arthur J. Moss,Jeffrey A. Towbin,Mark T. Keating +10 more
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Journal ArticleDOI
De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.
L Claes,Jurgen Del-Favero,Berten Ceulemans,Lieven Lagae,Christine Van Broeckhoven,Peter De Jonghe +5 more
TL;DR: Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+) and seven unrelated patients with SMEI were screened for mutations.