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.

Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

Abstract

SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage–sensitive synaptic pathway that is involved in autism spectrum disorders.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Genetic analyses of three families with ASD and SHANK3 mutations.
Figure 2: Localization of rare nonsynonymous variations or truncating SHANK3 mutations identified in families with ASD.

References

  1. Folstein, S.E. & Rosen-Sheidley, B. Nat. Rev. Genet. 2, 943–955 (2001).

    CAS  Article  Google Scholar 

  2. Persico, A.M. & Bourgeron, T. Trends Neurosci. 29, 349–358 (2006).

    CAS  Article  Google Scholar 

  3. Vorstman, J.A. et al. Mol. Psychiatry 11, 1, 18–28 (2006).

    CAS  Article  Google Scholar 

  4. Manning, M.A. et al. Pediatrics 114, 451–457 (2004).

    Article  Google Scholar 

  5. Bonaglia, M.C. et al. J. Med. Genet. 43, 822–828 (2006).

    CAS  Article  Google Scholar 

  6. Naisbitt, S. et al. Neuron 23, 569–582 (1999).

    CAS  Article  Google Scholar 

  7. Boeckers, T.M., Bockmann, J., Kreutz, M.R. & Gundelfinger, E.D. J. Neurochem. 81, 903–910 (2002).

    CAS  Article  Google Scholar 

  8. Meyer, G., Varoqueaux, F., Neeb, A., Oschlies, M. & Brose, N. Neuropharmacology 47, 724–733 (2004).

    CAS  Article  Google Scholar 

  9. Jamain, S. et al. Nat. Genet. 34, 27–29 (2003).

    CAS  Article  Google Scholar 

  10. Bonaglia, M.C. et al. Am. J. Hum. Genet. 69, 261–268 (2001).

    CAS  Article  Google Scholar 

  11. Roussignol, G. et al. J. Neurosci. 25, 3560–3570 (2005).

    CAS  Article  Google Scholar 

  12. Baron, M.K. et al. Science 311, 531–535 (2006).

    CAS  Article  Google Scholar 

  13. Lai, C.S., Fisher, S.E., Hurst, J.A., Vargha-Khadem, F. & Monaco, A.P. Nature 413, 519–523 (2001).

    CAS  Article  Google Scholar 

  14. Somerville, M.J. et al. N. Engl. J. Med. 353, 1694–1701 (2005).

    CAS  Article  Google Scholar 

  15. Carlisle, H.J. & Kennedy, M.B. Trends Neurosci. 28, 182–187 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the affected individuals and their families for participating in this study and all the collaborators of the Paris Autism Research International Sibpair Study: C. Gillberg, M. Råstam, I.C. Gillberg, G. Nygren, H. Anckarsäter and O. Ståhlberg (Department of Child and Adolescent Psychiatry, Göteborg University); M. Leboyer (Department of Psychiatry, Groupe Hospitalier Albert Chenevier et Henri Mondor); C. Betancur (INSERM U513, Université Paris XII); C. Colineaux, D. Cohen, N. Chabane and M.-C. Mouren-Siméoni (Service de Psychopathologie de l'Enfant et l'Adolescent, Hôpital Robert Debré); A. Brice (INSERM U679, Hôpital Pitié-Salpêtrière); E. Sponheim (Centre for Child and Adolescent Psychiatry, University of Oslo); O.H. Skjeldal (Department of Pediatrics, Rikshospitalet, University of Oslo); M. Coleman (Department of Pediatrics, Georgetown University School of Medicine); P.L. Pearl (Children's National Medical Center, George Washington University School of Medicine); I.L. Cohen and J. Tsiouris (New York State Institute for Basic Research in Developmental Disabilities); Michele Zappella (Divisione di Neuropsichiatria Infantile, Azienda Ospedaliera Senese); H. Aschauer (Department of General Psychiatry, University Hospital, Vienna) and L. Van Maldergem (Centre de Génétique Humaine, Institut de Pathologie et de Génétique). We also thank the DNA and cell bank of INSERM U679 (IFR des Neurosciences, Hôpital Pitié-Salpêtrière); the Centre d'Investigations Cliniques of the Hôpital Robert Debré; C. Bouchier and S. Duthoy for the use of sequencing facilities at the Génopole Pasteur and A. Hchikat, L. Margarit and G. Rouffet for technical assistance. This work was supported by the Pasteur Institute, INSERM, Assistance Publique-Hôpitaux de Paris, Fondation France Télécom, Cure Autism Now, Fondation de France, Fondation Biomédicale de la Mairie de Paris, Fondation pour la Recherche Médicale, EUSynapse European Commission FP6, AUTISM MOLGEN European Commission FP6, Fondation NRJ, the Swedish Science Council and the Deutsche Forschungsgemeinschaft DFG, SFB 497.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas Bourgeron.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Genomic structure and mRNA expression of the human SHANK3 gene. (PDF 1208 kb)

Supplementary Fig. 2

Genomic sequence of the deletion breakpoint in family ASD 1 and prediction of quadruplex-forming G-rich sequences (QGRS) at the terminal end of chromosome 22q13. (PDF 118 kb)

Supplementary Fig. 3

Pedigree structure, haplotype analyses and conservation of the SHANK3 mutations and variants identified in individuals with autism. (PDF 495 kb)

Supplementary Fig. 4

Analyses of SHANK3 mutations in rat hippocampal neuronal cultures. (PDF 168 kb)

Supplementary Table 1

SHANK3 variations identified in families with ASD and controls. (PDF 39 kb)

Supplementary Table 2

Primers used in this study. (PDF 43 kb)

Supplementary Methods (PDF 85 kb)

Supplementary Note (PDF 91 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Durand, C., Betancur, C., Boeckers, T. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39, 25–27 (2007). https://doi.org/10.1038/ng1933

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1933

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing