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Genetic Ablation of GIGYF1, Associated With Autism, Causes Behavioral and Neurodevelopmental Defects in Zebrafish and
Zijiao Ding1, Guiyang Huang2, Tianyun Wang3
1Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, China.
Background:
Autism spectrum disorder is characterized by deficits in social communication and restricted or repetitive behaviors. Due to the extremely high genetic and phenotypic heterogeneity, it is critical to pinpoint the genetic factors for understanding the pathology of these disorders.
Methods:
We analyzed the exomes generated by the SPARK (Simons Powering Autism Research) project and performed a meta-analysis with previous data. We then generated 1 zebrafish knockout model and 3 mouse knockout models to examine the function of GIGYF1 in neurodevelopment and behavior. Finally, we performed whole tissue and single-nucleus transcriptome analysis to explore the molecular and cellular function of GIGYF1.
Results:
GIGYF1 variants are significantly associated with various neurodevelopmental disorder phenotypes, including autism, global developmental delay, intellectual disability, and sleep disturbance. Loss of GIGYF1 causes similar behavioral effects in zebrafish and mice, including elevated levels of anxiety and reduced social engagement, which is reminiscent of the behavioral deficits in human patients carrying GIGYF1 variants. Moreover, excitatory neuron-specific Gigyf1 knockout mice recapitulate the increased repetitive behaviors and impaired social memory, suggesting a crucial role of Gigyf1 in excitatory neurons, which correlates with the observations in single-nucleus RNA sequencing. We also identified a series of downstream target genes of GIGYF1 that affect many aspects of the nervous system, especially synaptic transmission.
Conclusions:
De novo variants of GIGYF1 are associated with neurodevelopmental disorders, including autism spectrum disorder. GIGYF1 is involved in neurodevelopment and animal behavior, potentially through regulating hippocampal CA2 neuronal numbers and disturbing synaptic transmission.
