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KDM5A mutations identified in autism spectrum disorder using forward genetics
Lauretta El Hayek1, Islam Oguz Tuncay2, Nadine Nijem1
1Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.
Elife
|December 22, 2020
Summary
Researchers identified KDM5A as a gene linked to autism spectrum disorder (ASD). Mouse models and human patients showed that KDM5A gene mutations cause ASD symptoms, including speech deficits.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Autism spectrum disorder (ASD) presents significant genetic and phenotypic heterogeneity, challenging the identification of causative genes.
- Forward genetics approaches are valuable for discovering genes involved in complex neurodevelopmental disorders.
Observation:
- A forward genetics screen in mice identified KDM5A as a candidate gene associated with defective vocalization.
- KDM5A knockout mice (KDM5A-/-) exhibited disrupted vocalization, repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphology.
Findings:
- Inactivating KDM5A in mice led to significant dysregulation of the hippocampal transcriptome.
- Pathogenic KDM5A variants were identified in nine human patients diagnosed with ASD and speech impairment.
Implications:
- This study highlights KDM5A's critical role in normal brain development and function.
- The findings underscore the effectiveness of forward genetics in identifying novel ASD-associated genes.
- KDM5A emerges as a potential therapeutic target for specific forms of ASD.
