Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

Autor: Griesi-Oliveira K; 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., Acab A; 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., Gupta AR; Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA., Sunaga DY; Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil., Chailangkarn T; 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., Nicol X; Division of Biological Sciences, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA., Nunez Y; 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., Walker MF; Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA., Murdoch JD; Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA., Sanders SJ; Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA., Fernandez TV; Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA., Ji W; Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA., Lifton RP; Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA., Vadasz E; Instituto de Psiquiatria do Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil., Dietrich A; Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, Germany., Pradhan D; Institute for Cell Engineering, The Solomon H Snyder Department of Neuroscience/Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Song H; Institute for Cell Engineering, The Solomon H Snyder Department of Neuroscience/Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Ming GL; Institute for Cell Engineering, The Solomon H Snyder Department of Neuroscience/Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Gu X; Department of Pediatrics/Rady Children's Hospital San Diego, Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA., Haddad G; Department of Pediatrics/Rady Children's Hospital San Diego, Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA., Marchetto MC; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA., Spitzer N; Division of Biological Sciences, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA., Passos-Bueno MR; Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil., State MW; Program on Neurogenetics, Child Study Center, Departments of Genetics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA., Muotri AR; 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.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2015 Nov; Vol. 20 (11), pp. 1350-65. Date of Electronic Publication: 2014 Nov 11.
DOI: 10.1038/mp.2014.141
Abstrakt: 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.
Databáze: MEDLINE
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