Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures.
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.
Mantegazza
Massimo
M
Department of Neurophysiopathogy, Istituto Neurologico C. Besta, Milan, Italy. mmantegazza@istituto-besta.it
Gambardella
Antonio
A
Rusconi
Raffaella
R
Schiavon
Emanuele
E
Annesi
Ferdinanda
F
Cassulini
Rita Restano
RR
Labate
Angelo
A
Carrideo
Sara
S
Chifari
Rosanna
R
Canevini
Maria Paola
MP
Canger
Raffaele
R
Franceschetti
Silvana
S
Annesi
Grazia
G
Wanke
Enzo
E
Quattrone
Aldo
A
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*
D017931:DNA Primers; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels