Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Lord C, Cook EH, Leventhal BL, Amaral DG . Autism spectrum disorders. Neuron 2000; 28: 355–363.

    CAS  Article  Google Scholar 

  2. Rapin I . Current concepts: autism. N Engl J Med 1997; 337: 97–104.

    CAS  Article  Google Scholar 

  3. Lewine JD, Andrews R, Chez M, Patil A-A, Devinsky O, Smith M et al. Magnetoenchephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. Pediatrics 1999; 104: 405–418.

    CAS  Article  Google Scholar 

  4. Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D et al. A genomewide screen for autism susceptibility loci. Am J Hum Genet 2001; 69: 327–340.

    CAS  Article  Google Scholar 

  5. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63–77.

    CAS  Article  Google Scholar 

  6. Lamb JA, Moore J, Bailey A, Monaco AP . Autism: recent molecular genetic advances. Hum Mol Genet 2000; 9: 861–868.

    CAS  Article  Google Scholar 

  7. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J et al. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999; 65: 493–507.

    CAS  Article  Google Scholar 

  8. Lam CW, Yeung WL, Ko CH, Poon PM, Tong SF, Chan KY et al. Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet 2000; 37: E41.

    CAS  Article  Google Scholar 

  9. Vourc'h P, Bienvenu T, Beldjord C, Chelly J, Barthelemy C, Muh JP et al. No mutations in the coding region of the Rett syndrome gene MECP2 in 59 autistic patients. Eur J Hum Genet 2001; 9: 556–558.

    CAS  Article  Google Scholar 

  10. International Molecular Genetic Study of Autism Consortium (IMGSAC). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet 1998; 7: 571–578.

  11. Philippe A, Martinez M, Guiloud-Bataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes. Hum Mol Genet 1999; 8: 805–812.

    CAS  Article  Google Scholar 

  12. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68: 1514–1520.

    CAS  Article  Google Scholar 

  13. IMGSAC. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.

  14. Shao Y, Raiford KL, Wolpert CM, Cope HA, Ravan SA, Ashley-Koch AA et al. Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet 2002; 70: 1058–1061.

    CAS  Article  Google Scholar 

  15. Escayg A, Heils A, MacDonald BT, Haug K, Sander T, Meisler MH . A novel GEFS+ mutation in sodium channel SCN1A and prevalence of variants in epilepsy patients. Am J Hum Genet 2001; 68: 866–873.

    CAS  Article  Google Scholar 

  16. Felts PA, Yokoyama S, Dib-Hajj S, Black JA, Waxman SG . Sodium channel α-subunit mRNAs I, II, III, NaG, Na6 and hNE (PN1); different expression patterns in developing rat nervous system. Mol Brain Res 1997; 45: 71–82.

    CAS  Article  Google Scholar 

  17. Whitaker WR, Clare JJ, Powell AJ, Chen YH, Faull RL, Emson PC . Distribution of voltage-gated sodium channel alpha-subunit and beta-subunit mRNAs in human hippocampal formation, cortex, and cerebellum. J Comp Neurol 2000; 422: 123–139.

    CAS  Article  Google Scholar 

  18. Plummer NW, Meisler MH . Evolution and diversity of mammalian sodium channel genes. Genomics 1999; 57: 323–331.

    CAS  Article  Google Scholar 

  19. Meisler MH, Kearney J, Ottman R, Escayg A . Identification of epilepsy genes in human and mouse. Annu Rev Genet 2001; 35: 567–588.

    CAS  Article  Google Scholar 

  20. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P . De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001; 68: 1327–1332.

    CAS  Article  Google Scholar 

  21. Kearney JA, Plummer NW, Smith MR, Kapur J, Cummins TR, Waxman SG et al. A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience 2001; 102: 307–317.

    CAS  Article  Google Scholar 

  22. Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 2001; 69: 463–466.

    CAS  Article  Google Scholar 

  23. Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I et al. Mutations of SCN1A, encoding a neuronal sodium channel in two families with GEFS+2. Nat Genet 2000; 24: 343–345.

    CAS  Article  Google Scholar 

  24. Escayg A, Jones JM, Kearney JA, Hitchcock PF, Meisler MH . Calcium channel β4 (CACNB4): human ortholog of the mouse epilepsy gene lethargic. Genomics 1998; 50: 14–22.

    CAS  Article  Google Scholar 

  25. Mori M, Konno T, Ozawa T, Murata M, Imoto K, Nagayama K . Novel interaction of the voltage-dependent sodium channel (VDSC) with calmodulin: does VDSC acquire calmodulin-mediated Ca2+-sensitivity. Biochemistry 2000; 39: 1316–1323.

    CAS  Article  Google Scholar 

  26. Gaur RK, McLaughlin LW, Green MR . Functional group substitutions of the branchpoint adenosine in a nuclear pre-mRNA and a group II intron. RNA 1997; 3: 861–869.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lund M, Tange TO, Dyhr-Mikkelsen H, Hansen J, Kjems J . Characterization of human RNA splice signals by iterative functional selection of splice sites. RNA 2000; 6: 528–544.

    CAS  Article  Google Scholar 

  28. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001; 68: 598–605.

    CAS  Article  Google Scholar 

  29. Rook MB, Alshinawi CB, Groenewegen WA et al. Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovasc Res 1999; 44: 507–517.

    CAS  Article  Google Scholar 

  30. Raman IM, Sprunger LK, Meisler MH, Bean BP . Altered subthreshold sodium currents and disrupted firing patterns in purkinje neurons of Scn8a mutant mice. Neuron 1997; 19: 881–891.

    CAS  Article  Google Scholar 

  31. Meisler MH, Kearney J, Escayg A, MacDonald BT, Sprunger LK . Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. Neuroscientist 2001; 7: 136–145.

    CAS  Article  Google Scholar 

  32. Spampanato J, Escayg A, Meisler MH, Goldin AL . Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J Neurosci 2001; 21: 7481–7490.

    CAS  Article  Google Scholar 

  33. Pritchard JK . Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001; 69: 124–137.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the resources provided by the participating AGRE families. This work was supported by the Wilson Family Research Foundation, The Seaver Autism Research Center, and Cure Autism Now. Fellowship support was provided by National Research Service Award NS10692 (JK) and the Genetics Training Program at the University of Michigan (T32 GM07544) (BM).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M H Meisler.

Additional information

The AGRE Consortium:22 AGRE Scientific Advisory Board, Chairman, DH Geschwind, MD, PhD, UCLA, Los Angeles, CA, Members, M Bucan, PhD, University of Pennsylvania, Philadelphia, PA; WT Brown, MD, PhD, FACMG, NYS Institute for Basic Research in Developmental Disabilities, Long Island, NY; JD Buxbaum, PhD, Mt Sinai School of Medicine, New York; TC Gilliam, PhD, Columbia Genome Center, New York; DA Greenberg, PhD, Mt Sinai Medical Center, New York; DH Ledbetter, PhD, University of Chicago, Chicago, IL; B Miller, MD, UCSF, San Francisco, CA; SF Nelson, MD, UCLA School of Medicine, Los Angeles, CA; J Pevsner, PhD, Kennedy Krieger Institute, Baltimore, MD; JI Rotter, MD, Cedars-Sinai Medical Center, Los Angeles, CA; GD Schellenberg, PhD, University of Washington, Seattle, WA; CA Sprouse, EdD, Children's National Medical Center, Baltimore, MD; RE Tanzi, PhD, Massachusetts General Hospital, Boston, MA; KC Wilhelmsen, MD, PhD, University of California, San Francisco, CA, and AGRE Collaborator: JM Silverman, PhD, Mt Sinai Medical School, New York, NY.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weiss, L., Escayg, A., Kearney, J. et al. Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Mol Psychiatry 8, 186–194 (2003). https://doi.org/10.1038/sj.mp.4001241

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001241

Keywords

  • sodium channel
  • autism
  • genetic susceptibility
  • neurogenetics
  • Chr 2
  • calmodulin

Further reading

Search

Quick links