De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia
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...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 17; pp. 7863 - 7868 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
27.04.2010
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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. 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. 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. [PUBLICATION ABSTRACT] 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.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. |
| Author | Noreau, Anne Côté, Mélanie Stone, Eric A. Hamdan, Fadi F. Spiegelman, Dan Krebs, Marie-Odile Marineau, Claude Lapointe, Mathieu Néri, Christian Mouaffak, Fayçal Rouleau, Guy A. Lafrenière, Ronald G. Peng, Huashan Fathalli, Ferid Samuels, Mark E. Barker, Philip A. Housman, David E. Carbonetto, Salvatore Gauthier, Julie Dubé, Marie-Pierre DeLisi, Lynn E. Xiong, Lan Awadalla, Philip Addington, Anjené M. Brustein, Edna Joober, Ridha the S2D Team Rapoport, Judith L. Drapeau, Pierre Haghighi, Ali P. Champagne, Nathalie |
| Author_xml | – sequence: 1 givenname: Julie surname: Gauthier fullname: Gauthier, Julie – sequence: 2 givenname: Nathalie surname: Champagne fullname: Champagne, Nathalie – sequence: 3 givenname: Ronald G. surname: Lafrenière fullname: Lafrenière, Ronald G. – sequence: 4 givenname: Lan surname: Xiong fullname: Xiong, Lan – sequence: 5 givenname: Dan surname: Spiegelman fullname: Spiegelman, Dan – sequence: 6 givenname: Edna surname: Brustein fullname: Brustein, Edna – sequence: 7 givenname: Mathieu surname: Lapointe fullname: Lapointe, Mathieu – sequence: 8 givenname: Huashan surname: Peng fullname: Peng, Huashan – sequence: 9 givenname: Mélanie surname: Côté fullname: Côté, Mélanie – sequence: 10 givenname: Anne surname: Noreau fullname: Noreau, Anne – sequence: 11 givenname: Fadi F. surname: Hamdan fullname: Hamdan, Fadi F. – sequence: 12 givenname: Anjené M. surname: Addington fullname: Addington, Anjené M. – sequence: 13 givenname: Judith L. surname: Rapoport fullname: Rapoport, Judith L. – sequence: 14 givenname: Lynn E. surname: DeLisi fullname: DeLisi, Lynn E. – sequence: 15 givenname: Marie-Odile surname: Krebs fullname: Krebs, Marie-Odile – sequence: 16 givenname: Ridha surname: Joober fullname: Joober, Ridha – sequence: 17 givenname: Ferid surname: Fathalli fullname: Fathalli, Ferid – sequence: 18 givenname: Fayçal surname: Mouaffak fullname: Mouaffak, Fayçal – sequence: 19 givenname: Ali P. surname: Haghighi fullname: Haghighi, Ali P. – sequence: 20 givenname: Christian surname: Néri fullname: Néri, Christian – sequence: 21 givenname: Marie-Pierre surname: Dubé fullname: Dubé, Marie-Pierre – sequence: 22 givenname: Mark E. surname: Samuels fullname: Samuels, Mark E. – sequence: 23 givenname: Claude surname: Marineau fullname: Marineau, Claude – sequence: 24 givenname: Eric A. surname: Stone fullname: Stone, Eric A. – sequence: 25 givenname: Philip surname: Awadalla fullname: Awadalla, Philip – sequence: 26 givenname: Philip A. surname: Barker fullname: Barker, Philip A. – sequence: 27 givenname: Salvatore surname: Carbonetto fullname: Carbonetto, Salvatore – sequence: 28 givenname: Pierre surname: Drapeau fullname: Drapeau, Pierre – sequence: 29 givenname: Guy A. surname: Rouleau fullname: Rouleau, Guy A. – sequence: 30 fullname: the S2D Team – sequence: 31 givenname: David E. surname: Housman fullname: Housman, David E. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/20385823$$D View this record in MEDLINE/PubMed |
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| Contributor | Laliberté, Guy Tsurudome, Kazuya Lachapelle, Karine Henrion, Edouard Thibodeau, Pascale Leroy, Sophie Liao, Meijiang Piton, Amélie Yang, Yan Duguay, Joannie Laurent, Sandra Reynolds, Annie Diallo, Ousmane Kuku, Frédéric Chayet, Mélanie Peng, Huashan Daignault, Kathleen Drits, Marina Rochefort, Daniel Marino, Carlos St-Onge, Judith Jolivet, Philippe Raymond, Annie Ossian, Katia Gourion, David |
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| Copyright | Copyright National Academy of Sciences Apr 27, 2010 |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Author contributions: C.N., M.E.S., C.M., P.A.B., S.C., P.D., and G.A.R. designed research; J.G., N.C., E.B., A.M.A., J.L.R., L.E.D., M.-O.K., R.J., F.F., F.M., A.P.H., and S2D Team performed research; E.A.S. and P.A. contributed new reagents/analytic tools; J.G., N.C., L.X., D.S., M.L., H.P., M.C., A.N., F.F.H., and M.-P.D. analyzed data; and J.G., N.C., and R.G.L. wrote the paper. Edited* by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, and approved March 15, 2010 (received for review June 4, 2009) |
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| Snippet | Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls... |
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| SubjectTerms | 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 |
| Title | De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia |
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