title: A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.
abstract: A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a(N641Y/N641Y) knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na(v)1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na(v)1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America. nsingh@genetics.utah.edu
authors.forename: Nanda A
authors.initials: NA
authors.lastname: Singh
authors.forename: Chris
authors.initials: C
authors.lastname: Pappas
authors.forename: E Jill
authors.initials: EJ
authors.lastname: Dahle
authors.forename: Lieve R F
authors.initials: LR
authors.lastname: Claes
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Joel
authors.initials: J
authors.lastname: Thompson
authors.forename: Missy
authors.initials: M
authors.lastname: Dixon
authors.forename: Christina
authors.initials: C
authors.lastname: Gurnett
authors.forename: Andy
authors.initials: A
authors.lastname: Peiffer
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Francis
authors.initials: F
authors.lastname: Filloux
authors.forename: Mark F
authors.initials: MF
authors.lastname: Leppert
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004597:Electroshock; D004827:Epilepsy / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D007696:Kindling, Neurologic / Q000502:physiology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D021122:Protein Subunits / Q000235:genetics; D003294:Seizures, Febrile / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D016415:Sequence Alignment; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C568242:SCN1A protein, human; C486866:SCN9A protein, human; C568249:Scn1a protein, mouse; D015222:Sodium Channels