title: Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures.
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.
authors.affiliation: Department of Neurophysiopathogy, Istituto Neurologico C. Besta, Milan, Italy. mmantegazza@istituto-besta.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
authors.forename: Antonio
authors.initials: A
authors.lastname: Gambardella
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rusconi
authors.forename: Emanuele
authors.initials: E
authors.lastname: Schiavon
authors.forename: Ferdinanda
authors.initials: F
authors.lastname: Annesi
authors.forename: Rita Restano
authors.initials: RR
authors.lastname: Cassulini
authors.forename: Angelo
authors.initials: A
authors.lastname: Labate
authors.forename: Sara
authors.initials: S
authors.lastname: Carrideo
authors.forename: Rosanna
authors.initials: R
authors.lastname: Chifari
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Canevini
authors.forename: Raffaele
authors.initials: R
authors.lastname: Canger
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.forename: Enzo
authors.initials: E
authors.lastname: Wanke
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005260:Female; D006801:Humans; D007558:Italy; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D003294:Seizures, Febrile / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D017931:DNA Primers; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels