Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.
An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.
Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California San Diego, School of Medicine, La Jolla, CA, USA.|Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil.
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Griesi-Oliveira
Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Acab
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
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Gupta
Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil.
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Sunaga
Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Chailangkarn
Division of Biological Sciences, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA.
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Nicol
Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Nunez
Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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Walker
Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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Murdoch
Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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Sanders
Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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Fernandez
Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
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Ji
Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
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Lifton
Instituto de Psiquiatria do Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.
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Vadasz
Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, Germany.
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Dietrich
Institute for Cell Engineering, The Solomon H Snyder Department of Neuroscience/Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Pradhan
Institute for Cell Engineering, The Solomon H Snyder Department of Neuroscience/Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Song
Institute for Cell Engineering, The Solomon H Snyder Department of Neuroscience/Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Ming
Department of Pediatrics/Rady Children's Hospital San Diego, Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Gu
Department of Pediatrics/Rady Children's Hospital San Diego, Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Haddad
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
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Marchetto
Division of Biological Sciences, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA.
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Spitzer
Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil.
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Passos-Bueno
Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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State
Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Muotri
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism; D001321:Autistic Disorder / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016190:Carboplatin / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005047:Etoposide / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008942:Mitoxantrone / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011239:Prednisolone / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D005047:Etoposide; D011239:Prednisolone; D016190:Carboplatin; D008942:Mitoxantrone