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


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.

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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.

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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.

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Correspondence to Thomas Bourgeron.

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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)

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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).

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