KDM5A mutations identified in autism spectrum disorder using forward genetics
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 ge...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/56883 |
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doaj-3b67c7165102417c8a9b719959887f98 |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 KDM5A mutations identified in autism spectrum disorder using forward genetics eLife autism spectrum disorder forward genetics chromatin regulator vocalization histone demethylase |
| author_facet |
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 |
| author_sort |
Lauretta El Hayek |
| title |
KDM5A mutations identified in autism spectrum disorder using forward genetics |
| title_short |
KDM5A mutations identified in autism spectrum disorder using forward genetics |
| title_full |
KDM5A mutations identified in autism spectrum disorder using forward genetics |
| title_fullStr |
KDM5A mutations identified in autism spectrum disorder using forward genetics |
| title_full_unstemmed |
KDM5A mutations identified in autism spectrum disorder using forward genetics |
| title_sort |
kdm5a mutations identified in autism spectrum disorder using forward genetics |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2020-12-01 |
| description |
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. |
| topic |
autism spectrum disorder forward genetics chromatin regulator vocalization histone demethylase |
| url |
https://elifesciences.org/articles/56883 |
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doaj-3b67c7165102417c8a9b719959887f982021-05-05T21:53:10ZengeLife Sciences Publications LtdeLife2050-084X2020-12-01910.7554/eLife.56883KDM5A mutations identified in autism spectrum disorder using forward geneticsLauretta El Hayek0https://orcid.org/0000-0002-6820-9316Islam Oguz Tuncay1Nadine Nijem2Jamie Russell3Sara Ludwig4Kiran Kaur5Xiaohong Li6Priscilla Anderton7Miao Tang8Amanda Gerard9Anja Heinze10Pia Zacher11Hessa S Alsaif12Aboulfazl Rad13https://orcid.org/0000-0001-8627-8828Kazem Hassanpour14Mohammad Reza Abbaszadegan15Camerun Washington16Barbara R DuPont17Raymond J Louie18CAUSES Study19Madeline Couse20Maha Faden21R Curtis Rogers22Rami Abou Jamra23Ellen R Elias24Reza Maroofian25Henry Houlden26Anna Lehman27Bruce Beutler28Maria H Chahrour29https://orcid.org/0000-0002-3174-1480Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United StatesEugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesEugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Texas Children’s Hospital, Houston, United StatesInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, GermanyInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; The Saxon Epilepsy Center Kleinwachau, Radeberg, GermanyDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi ArabiaCellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of IranNon-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of IranPardis 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 IranGreenwood Genetic Center, Greenwood, United StatesGreenwood Genetic Center, Greenwood, United StatesGreenwood Genetic Center, Greenwood, United StatesDepartment of Medical Genetics, University of British Columbia, British Columbia Children’s and Women’s Hospital Research Institute, Vancouver, CanadaDepartment of Medical Genetics, University of British Columbia, British Columbia Children’s and Women’s Hospital Research Institute, Vancouver, CanadaDepartment of Genetics, King Saud Medical City, Riyadh, Saudi ArabiaGreenwood Genetic Center, Greenwood, United StatesInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, GermanyDepartment of Pediatrics and Genetics, University of Colorado School of Medicine, Aurora, United StatesDepartment of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United KingdomDepartment of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United KingdomDepartment of Medical Genetics, University of British Columbia, British Columbia Children’s and Women’s Hospital Research Institute, Vancouver, CanadaCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesEugene 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 StatesAutism 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.https://elifesciences.org/articles/56883autism spectrum disorderforward geneticschromatin regulatorvocalizationhistone demethylase |