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KDM5A mutations identified in autism spectrum disorder using forward genetics.
El Hayek, Lauretta; Tuncay, Islam Oguz; Nijem, Nadine; Russell, Jamie; Ludwig, Sara; Kaur, Kiran; Li, Xiaohong; Anderton, Priscilla; Tang, Miao; Gerard, Amanda; Heinze, Anja; Zacher, Pia; Alsaif, Hessa S; Rad, Aboulfazl; Hassanpour, Kazem; Abbaszadegan, Mohammad Reza; Washington, Camerun; DuPont, Barbara R; Louie, Raymond J; Couse, Madeline; Faden, Maha; Rogers, R Curtis; Abou Jamra, Rami; Elias, Ellen R; Maroofian, Reza; Houlden, Henry; Lehman, Anna; Beutler, Bruce; Chahrour, Maria H.
Afiliação
  • El Hayek L; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.
  • Tuncay IO; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States.
  • Nijem N; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.
  • Russell J; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States.
  • Ludwig S; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States.
  • Kaur K; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.
  • Li X; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States.
  • Anderton P; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States.
  • Tang M; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States.
  • Gerard A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
  • Heinze A; Texas Children's Hospital, Houston, United States.
  • Zacher P; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
  • Alsaif HS; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
  • Rad A; The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany.
  • Hassanpour K; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
  • Abbaszadegan MR; Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of Iran.
  • Washington C; Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of Iran.
  • DuPont BR; Pardis Clinical and Genetics Laboratory, Mashhad, Islamic Republic of Iran.
  • Louie RJ; Division of Human Genetics, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran.
  • Couse M; Greenwood Genetic Center, Greenwood, United States.
  • Faden M; Greenwood Genetic Center, Greenwood, United States.
  • Rogers RC; Department of Medical Genetics, University of British Columbia, British Columbia Children's and Women's Hospital Research Institute, Vancouver, Canada.
  • Abou Jamra R; Department of Medical Genetics, University of British Columbia, British Columbia Children's and Women's Hospital Research Institute, Vancouver, Canada.
  • Elias ER; Department of Genetics, King Saud Medical City, Riyadh, Saudi Arabia.
  • Maroofian R; Greenwood Genetic Center, Greenwood, United States.
  • Houlden H; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
  • Lehman A; Department of Pediatrics and Genetics, University of Colorado School of Medicine, Aurora, United States.
  • Beutler B; Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United Kingdom.
  • Chahrour MH; Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United Kingdom.
Elife ; 92020 12 22.
Article em En | MEDLINE | ID: mdl-33350388
ABSTRACT
Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as a candidate ASD gene. To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if KDM5A mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína 2 de Ligação ao Retinoblastoma / Transtorno do Espectro Autista Tipo de estudo: Prognostic_studies Limite: Adolescent / Animals / Child, preschool / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína 2 de Ligação ao Retinoblastoma / Transtorno do Espectro Autista Tipo de estudo: Prognostic_studies Limite: Adolescent / Animals / Child, preschool / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article