eLife (Dec 2020)
KDM5A mutations identified in autism spectrum disorder using forward genetics
- Lauretta El Hayek,
- Islam Oguz Tuncay,
- Nadine Nijem,
- Jamie Russell,
- Sara Ludwig,
- Kiran Kaur,
- Xiaohong Li,
- Priscilla Anderton,
- Miao Tang,
- Amanda Gerard,
- Anja Heinze,
- Pia Zacher,
- Hessa S Alsaif,
- Aboulfazl Rad,
- Kazem Hassanpour,
- Mohammad Reza Abbaszadegan,
- Camerun Washington,
- Barbara R DuPont,
- Raymond J Louie,
- CAUSES Study,
- Madeline Couse,
- Maha Faden,
- R Curtis Rogers,
- Rami Abou Jamra,
- Ellen R Elias,
- Reza Maroofian,
- Henry Houlden,
- Anna Lehman,
- Bruce Beutler,
- Maria H Chahrour
Affiliations
- Lauretta El Hayek
- ORCiD
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
- Islam Oguz Tuncay
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
- Nadine Nijem
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
- Jamie Russell
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Sara Ludwig
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Kiran Kaur
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
- Xiaohong Li
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Priscilla Anderton
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Miao Tang
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Amanda Gerard
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Texas Children’s Hospital, Houston, United States
- Anja Heinze
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
- Pia Zacher
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany
- Hessa S Alsaif
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Aboulfazl Rad
- ORCiD
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of Iran
- Kazem Hassanpour
- Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of Iran
- Mohammad Reza Abbaszadegan
- Pardis Clinical and Genetics Laboratory, Mashhad, Islamic Republic of Iran; Division of Human Genetics, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran
- Camerun Washington
- Greenwood Genetic Center, Greenwood, United States
- Barbara R DuPont
- Greenwood Genetic Center, Greenwood, United States
- Raymond J Louie
- Greenwood Genetic Center, Greenwood, United States
- CAUSES Study
- Department of Medical Genetics, University of British Columbia, British Columbia Children’s and Women’s Hospital Research Institute, Vancouver, Canada
- Madeline Couse
- Department of Medical Genetics, University of British Columbia, British Columbia Children’s and Women’s Hospital Research Institute, Vancouver, Canada
- Maha Faden
- Department of Genetics, King Saud Medical City, Riyadh, Saudi Arabia
- R Curtis Rogers
- Greenwood Genetic Center, Greenwood, United States
- Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
- Ellen R Elias
- Department of Pediatrics and Genetics, University of Colorado School of Medicine, Aurora, United States
- Reza Maroofian
- Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United Kingdom
- Henry Houlden
- Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United Kingdom
- Anna Lehman
- Department of Medical Genetics, University of British Columbia, British Columbia Children’s and Women’s Hospital Research Institute, Vancouver, Canada
- Bruce Beutler
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Maria H Chahrour
- ORCiD
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United States; Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, United States
- DOI
- https://doi.org/10.7554/eLife.56883
- Journal volume & issue
-
Vol. 9
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.
Keywords
