De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 17; pp. 7863 - 7868
• Main Authors: Gauthier, Julie, Champagne, Nathalie, Lafrenière, Ronald G., Xiong, Lan, Spiegelman, Dan, Brustein, Edna, Lapointe, Mathieu, Peng, Huashan, Côté, Mélanie, Noreau, Anne, Hamdan, Fadi F., Addington, Anjené M., Rapoport, Judith L., DeLisi, Lynn E., Krebs, Marie-Odile, Joober, Ridha, Fathalli, Ferid, Mouaffak, Fayçal, Haghighi, Ali P., Néri, Christian, Dubé, Marie-Pierre, Samuels, Mark E., Marineau, Claude, Stone, Eric A., Awadalla, Philip, Barker, Philip A., Carbonetto, Salvatore, Drapeau, Pierre, Rouleau, Guy A., the S2D Team, Housman, David E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.04.2010; National Acad Sciences
• Subjects: Amino Acid Sequence; Animals; Autism; Base Sequence; Biological Sciences; Brothers; Carrier Proteins - genetics; Computational Biology; Danio rerio; DNA Primers - genetics; Environmental factors; Female; genes; Genetic loci; Genetic mutation; Genetics; Genotype & phenotype; germ cells; Humans; Intelligence quotient; Male; Medical genetics; Mental disorders; Messenger RNA; Microsatellite Repeats - genetics; Molecular Sequence Data; mutants; Mutation; Mutation, Missense - genetics; Nerve Tissue Proteins - genetics; Neurons; Neurons - cytology; Parents; patients; Pedigree; phenotype; Phenotypes; Proteins; Rats; scaffolding proteins; Schizophrenia; Schizophrenia - genetics; Sequence Analysis, DNA; Zebrafish
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0906232107

Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.