Referenced in: none

Automatically associated channels: Nav1.1

Title: Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures.

Authors: Massimo Mantegazza, Antonio Gambardella, Raffaella Rusconi, Emanuele Schiavon, Ferdinanda Annesi, Rita Restano Cassulini, Angelo Labate, Sara Carrideo, Rosanna Chifari, Maria Paola Canevini, Raffaele Canger, Silvana Franceschetti, Grazia Annesi, Enzo Wanke, Aldo Quattrone

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2005 Dec 13 , 102, 18177-82

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16326807

Abstract
Febrile seizures (FS) affect 5-12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures in approximately 7% of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomal-dominant locus has been identified on chromosome 2q23-24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Na(v)1.1 channel alpha-subunit cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy.