title: Sodium channels SCN1A, SCN2A and SCN3A in familial autism.
abstract: Autism is a psychiatric disorder with estimated heritability of 90%. One-third of autistic individuals experience seizures. A susceptibility locus for autism was mapped near a cluster of voltage-gated sodium channel genes on chromosome 2. Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS+. To evaluate these sodium channel genes as candidates for the autism susceptibility locus, we screened for variation in coding exons and splice sites in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of intron sequence were screened. Only six families carried variants with potential effects on sodium channel function. Five coding variants and one lariat branchpoint mutation were each observed in a single family, but were not present in controls. The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one autism family and had previously been identified in a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint mutation was tested in cultured lymphoblasts. Additional population studies and functional tests will be required to evaluate pathogenicity of the coding and lariat site variants. SNP density was 1/kb in the genomic sequence screened. We report 38 sodium channel SNPs that will be useful in future association and linkage studies.
authors.affiliation: Department of Human Genetics, University of Michigan, 4708 Medical Science II, Ann Arbor, MI 48109-0618, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Weiss
authors.forename: A
authors.initials: A
authors.lastname: Escayg
authors.forename: J A
authors.initials: JA
authors.lastname: Kearney
authors.forename: M
authors.initials: M
authors.lastname: Trudeau
authors.forename: B T
authors.initials: BT
authors.lastname: MacDonald
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: J
authors.initials: J
authors.lastname: Reichert
authors.forename: J D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: M H
authors.initials: MH
authors.lastname: Meisler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D005091:Exons; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568251:SCN2A protein, human; C424715:SCN3A protein, human; D015222:Sodium Channels