| Literature DB >> 33350388 |
Lauretta El Hayek1, Islam Oguz Tuncay2, Nadine Nijem1, Jamie Russell3, Sara Ludwig3, Kiran Kaur1, Xiaohong Li3, Priscilla Anderton3, Miao Tang3, Amanda Gerard4,5, Anja Heinze6, Pia Zacher6,7, Hessa S Alsaif8, Aboulfazl Rad9, Kazem Hassanpour10, Mohammad Reza Abbaszadegan11,12, Camerun Washington13, Barbara R DuPont13, Raymond J Louie13, Madeline Couse14, Maha Faden15, R Curtis Rogers13, Rami Abou Jamra6, Ellen R Elias16, Reza Maroofian17, Henry Houlden17, Anna Lehman14, Bruce Beutler3, Maria H Chahrour1,2,3,18,19.
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.Entities:
Keywords: autism spectrum disorder; chromatin regulator; forward genetics; genetics; genomics; histone demethylase; human; medicine; mouse; vocalization
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Year: 2020 PMID： 33350388 PMCID： PMC7755391 DOI： 10.7554/eLife.56883
Source DB: PubMed Journal: Elife ISSN： 2050-084X Impact factor: 8.140