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Complete Disruption of Autism-Susceptibility Genes by Gene Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons.
Deneault, Eric; White, Sean H; Rodrigues, Deivid C; Ross, P Joel; Faheem, Muhammad; Zaslavsky, Kirill; Wang, Zhuozhi; Alexandrova, Roumiana; Pellecchia, Giovanna; Wei, Wei; Piekna, Alina; Kaur, Gaganjot; Howe, Jennifer L; Kwan, Vickie; Thiruvahindrapuram, Bhooma; Walker, Susan; Lionel, Anath C; Pasceri, Peter; Merico, Daniele; Yuen, Ryan K C; Singh, Karun K; Ellis, James; Scherer, Stephen W.
Afiliação
  • Deneault E; Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • White SH; Stem Cell and Cancer Research Institute, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton L8S 4L8, Canada.
  • Rodrigues DC; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Ross PJ; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Faheem M; Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Zaslavsky K; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3H7, Canada.
  • Wang Z; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Alexandrova R; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Pellecchia G; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Wei W; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Piekna A; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Kaur G; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Howe JL; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Kwan V; Stem Cell and Cancer Research Institute, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton L8S 4L8, Canada.
  • Thiruvahindrapuram B; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Walker S; Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Lionel AC; Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Pasceri P; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Merico D; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Yuen RKC; Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Singh KK; Stem Cell and Cancer Research Institute, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton L8S 4L8, Canada. Electronic address: singhk2@mcmaster.ca.
  • Ellis J; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3H7, Canada. Electronic address: jellis@sickkids.ca.
  • Scherer SW; Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3H7, Canada; McLaughlin Centre, U
Stem Cell Reports ; 11(5): 1211-1225, 2018 11 13.
Article em En | MEDLINE | ID: mdl-30392976
ABSTRACT
Autism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNA sequencing revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory postsynaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2-, and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtorno Autístico / Predisposição Genética para Doença / Edição de Genes / Neurônios Limite: Humans Idioma: En Revista: Stem Cell Reports Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtorno Autístico / Predisposição Genética para Doença / Edição de Genes / Neurônios Limite: Humans Idioma: En Revista: Stem Cell Reports Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Canadá