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.
|Titolo:||Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures|
|Parole Chiave:||channelopathy ; FEB3 locus ; convulsions ; epilepsy ; neuronal excitabilit|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
Settore MED/39 - Neuropsichiatria Infantile
|Data di pubblicazione:||dic-2005|
|Digital Object Identifier (DOI):||10.1073/pnas.0506818102|
|Appare nelle tipologie:||01 - Articolo su periodico|