Sodium channels SCN1A, SCN2A and SCN3A in familial autism

L. A. Weiss, A. Escayg, J. A. Kearney, M. Trudeau, B. T. MacDonald, M. Mori, J. Reichert, J. D. Buxbaum, M. H. Meisler*

*Corresponding author for this work

Research output: Contribution to journalArticle

203 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)186-194
Number of pages9
JournalMolecular Psychiatry
Volume8
Issue number2
DOIs
StatePublished - Mar 24 2003

Fingerprint

Sodium Channels
Autistic Disorder
Calmodulin
Mutation
Single Nucleotide Polymorphism
Juvenile Myoclonic Epilepsy
Genes
Voltage-Gated Sodium Channels
Chromosomes, Human, Pair 2
Introns
Psychiatry
Virulence
Exons
Epilepsy
Seizures
Binding Sites
Calcium
Population

Keywords

  • Autism
  • Calmodulin
  • Chr 2
  • Genetic susceptibility
  • Neurogenetics
  • Sodium channel

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Weiss, L. A., Escayg, A., Kearney, J. A., Trudeau, M., MacDonald, B. T., Mori, M., ... Meisler, M. H. (2003). Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Molecular Psychiatry, 8(2), 186-194. https://doi.org/10.1038/sj.mp.4001241
Weiss, L. A. ; Escayg, A. ; Kearney, J. A. ; Trudeau, M. ; MacDonald, B. T. ; Mori, M. ; Reichert, J. ; Buxbaum, J. D. ; Meisler, M. H. / Sodium channels SCN1A, SCN2A and SCN3A in familial autism. In: Molecular Psychiatry. 2003 ; Vol. 8, No. 2. pp. 186-194.
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Weiss, LA, Escayg, A, Kearney, JA, Trudeau, M, MacDonald, BT, Mori, M, Reichert, J, Buxbaum, JD & Meisler, MH 2003, 'Sodium channels SCN1A, SCN2A and SCN3A in familial autism', Molecular Psychiatry, vol. 8, no. 2, pp. 186-194. https://doi.org/10.1038/sj.mp.4001241

Sodium channels SCN1A, SCN2A and SCN3A in familial autism. / Weiss, L. A.; Escayg, A.; Kearney, J. A.; Trudeau, M.; MacDonald, B. T.; Mori, M.; Reichert, J.; Buxbaum, J. D.; Meisler, M. H.

In: Molecular Psychiatry, Vol. 8, No. 2, 24.03.2003, p. 186-194.

Research output: Contribution to journalArticle

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AU - Weiss, L. A.

AU - Escayg, A.

AU - Kearney, J. A.

AU - Trudeau, M.

AU - MacDonald, B. T.

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AU - Buxbaum, J. D.

AU - Meisler, M. H.

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N2 - 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.

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Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M et al. Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Molecular Psychiatry. 2003 Mar 24;8(2):186-194. https://doi.org/10.1038/sj.mp.4001241