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De Novo Mutations in the Gene Encoding the Synaptic Scaffolding Protein SHANK3 in Patients Ascertained for Schizophrenia

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De Novo Mutations in the Gene Encoding the Synaptic Scaffolding Protein SHANK3 in Patients Ascertained for Schizophrenia De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia Julie Gauthiera,1, Nathalie Champagneb, Ronald G. Lafrenièrea, Lan Xionga, Dan Spiegelmana, Edna Brusteinb, Mathieu Lapointeb, Huashan Pengb, Mélanie Côtéa, Anne Noreaua, Fadi F. Hamdanc, Anjené M. Addingtond, Judith L. Rapoportd, Lynn E. DeLisie, Marie-Odile Krebsf, Ridha Jooberg, Ferid Fathallig, Fayçal Mouaffakf, Ali P. Haghighih, Christian Nérii, Marie-Pierre Dubéj, Mark E. Samuelsc, Claude Marineaua, Eric A. Stonek, Philip Awadallal, Philip A. Barkerm, Salvatore Carbonettohn, Pierre Drapeaub, Guy A. Rouleaua,1, and the S2D Teama,b,c aCentre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l’Université de Montréal Research Center, and the Department of Medicine, Université de Montréal, Montréal, QC H2L 2W5, Canada; bDepartment of Pathology and Cell Biology and Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, QC H3T 1J4, Canada; cCentre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC H3T 1C5, Canada; dChild Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892-1600; eVeterans Administration Boston Healthcare System, Harvard Medical School, Brockton, MA 02301; fLaboratory of Pathophysiology of Psychiatric Diseases, Université Paris Descartes, U894, Sainte-Anne Hospital, 75014 Paris, France; gDouglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, QC H4H 1R3, Canada; hDepartment of Physiology, McGill University, Montréal, QC H3G 0B1, Canada; iINSERM, U857, Neuronal Cell Biology and Pathology, Centre Paul Broca, 75014 Paris, France; jCentre de Recherche, Institut de Cardiologie de Montréal, and Department of Pharmacology, Université de Montréal, Montréal, QC H1T 1C8, Canada; kBioinformatics Research, North Carolina State University, Raleigh, NC 27695-7566; lResearch Center, CHU Sainte- Justine, and Department of Pediatrics and Biochemistry, Université de Montréal, Montréal, QC H3T 1C5, Canada; mCentre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; and nCentre for Research in Neuroscience, McGill University Health Centre, Montréal General Hospital, Montréal, QC H3G 1A4, Canada Edited* by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, and approved March 15, 2010 (received for review June 4, 2009) Schizophrenia likely results from poorly understood genetic and SHANK3 screen the gene in our cohort of SCZ probands. Given GENETICS environmental factors. We studied the gene encoding the synaptic our hypothesis that a significant fraction of SCZ cases are the protein SHANK3 in 285 controls and 185 schizophrenia patients with result of new mutations, we selected SCZ cases with unaffected unaffected parents. Two de novo mutations (R1117X and R536W) parents and screened for de novo mutations. were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippo- Results campal neuron assays revealed behavior and differentiation defects We screened the coding region of the SHANK3 gene in 185 resulting from the R1117X mutant. As mutations in SHANK3 were unrelated SCZ probands (Table S1) and identified two unrelated previously reported in autism, the occurrence of SHANK3 mutations SCZ patients who were heterozygous for de novo mutations in subjects with a schizophrenia phenotype suggests a molecular (R1117X and R536W; Fig. 1). Parentage of proband/parent trios genetic link between these two neurodevelopmental disorders. and DNA authenticity in all family members were confirmed using a panel of microsatellite markers (Table S2). chizophrenia (SCZ) is a chronic psychiatric disorder charac- We detected a nonsense de novo R1117X mutation, in a pro- Sterized by a profound disruption in cognition, behavior, and band and his two affected brothers (Fig. 1A), which appeared to be emotion which begins in adolescence or early adulthood. There is inherited from the paternal strand based on haplotype analysis significant clinical variability among SCZ patients, suggesting that (Table S2) and is likely due to germline mosaicism. The proband it is etiologically heterogeneous. There are several hypotheses to (II-1) is of European ancestry and has a diagnosis of schizo- explain genetic factors underlying SCZ, such as polygenic inher- affective disorder (age of onset 19 years). This patient was con- itance (1) or, in a fraction of cases, variably penetrant de novo sidered suffering from borderline mental retardation (MR) since mutations. The de novo hypothesis is based on several observa- childhood but went through school and graduated from high tions. One is that relatives of an individual with SCZ have a higher school in a special educational program for children with intel- risk of being affected (parents 6%, offspring 13%, and siblings 9% lectual difficulties. He had a Wechsler Adult Intelligence Scale compared with 1% for the general population) (2). The greater verbal intelligence quotient (IQ) of 73, performance of 73, and frequency in offspring than in parents may occur if new mutations account for a fraction of SCZ cases. Also, there is a significantly increased risk of SCZ with increasing paternal age (3), which Author contributions: C.N., M.E.S., C.M., P.A.B., S.C., P.D., and G.A.R. designed research; could result from the age-related increase in paternal de novo 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 per- fi formed research; E.A.S. and P.A. contributed new reagents/analytic tools; J.G., N.C., L.X., mutations. Furthermore, despite reduced reproductive tness (4) 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. and extremely variable environmental factors, the incidence of wrote the paper. ∼ SCZ is maintained at 1% worldwide. Interestingly, recent The authors declare no conflict of interest. studies reported de novo copy-number variants in SCZ, providing The S2D team is composed of the following additional members: Kathleen Daignault, further support for the de novo mutation hypothesis (5, 6). Ousmane Diallo, Joannie Duguay, Marina Drits, Edouard Henrion, Philippe Jolivet, Fréd- As part of the Synapse to Disease (S2D) project aimed at éric Kuku, Karine Lachapelle, Guy Laliberté, Sandra Laurent, Meijiang Liao, Carlos Marino, exploring the de novo mutation hypothesis in brain diseases, we Huashan Peng, Amélie Piton, Annie Raymond, Annie Reynolds, Daniel Rochefort, Judith St-Onge, Pascale Thibodeau, Kazuya Tsurudome, Yan Yang, Sophie Leroy, Katia Ossian, are sequencing synaptic genes in individuals with SCZ and Mélanie Chayet, and David Gourion. autism spectrum disorder (ASD), two neurodevelopmental dis- *This Direct Submission article had a prearranged editor. SHANK3 orders. Recently, mutations in the (SH3 and multiple Freely available online through the PNAS open access option. ankyrin repeat domains 3) gene, encoding a scaffolding protein 1To whom correspondence may be addressed. E-mail: [email protected] or guy. abundant in the postsynaptic density of excitatory synapses on [email protected]. – dendritic spines, were found in patients with ASD (7 9). Con- This article contains supporting information online at www.pnas.org/cgi/content/full/ sidering that ASD and SCZ share some features, we decided to 0906232107/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0906232107 PNAS | April 27, 2010 | vol. 107 | no. 17 | 7863–7868 Downloaded by guest on September 27, 2021 A B Fig. 1. Families with de novo mutations in the SHANK3 gene. (A) Segregation of the R1117X nonsense mutation in three affected brothers of family PED 419. The proband is indicated by the arrow. (B) Segregation of the R536W missense mutation in the proband but not her unaffected brother in PED 56. (C) Localization on the linear protein structure of SHANK3 of the de novo mutations found in families with schizophrenia. ANK, ankyrin repeats; SH3, C Src homology 3 domain; PDZ, postsynaptic density protein (PSD95), Drosophila disk large tumor suppressor (DlgA), and zonula occludens-1 protein (zo-1) domain; SAM, sterile α motif domain. (D) Western blot analysis using HA antibody of HEK293T cell lysate transfected with empty vector (control), HA-Shank3 (WT), R1117X, and R536W. R536W D E * Shank3 WT and R536W have a similar size (200 kDa), SHANK3_Human EEVQMRQHDTRPETREDRTKR whereas the nonsense R1117X results in a truncated pro- SHANK3_Chimp EEVQMRQQPPRVETREDRTKR SHANK3_Rhesus EEVQMRQHDPRPETREDRTKR tein (123 kDa). (E) Alignment of SHANK3 orthologous SHANK3_Dog EEVQMRQYDTRHETREDRTKR peptide sequences near the R536W missense (indicated SHANK3_Rat EEVQMRQYDTRHETREDRTKR SHANK3_Mouse EEVQMRQYDTRHETREDRTKR by the asterisk showing amino acid conservation of the SHANK3_Opossum EEVQMRQYDTRHETREDRTKR R536 residues in 10 species). GenBank accession numbers: SHANK3_Lizard EEVQMRQFDPRQETREDRTKR SHANK3_Xenopus EEVQMRQPDPRQETREDRTKR chimp, AC145340; Rhesus monkey, AANU01101358; dog, SHANK3.1_Zebrafish EEVQMRQYDPRLETREDRTKR SHANK3.2_Zebrafish EEVQMRQYDPRLETREDRNKR XP_848271; rat, P_067708; opossum, XP_001366729; liz- ard, AAWZ01039630; Xenopus, CX494866; zebrafish: zs3.1, CAI20675 and zs3.2, XR_028926. full-scale of 72. He presents no evidence of any autistic features. new protein-truncating mutations, were detected in this control Brother
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