CONCLUSION: De novo variants (DNVs) of GIGYF1 are associated with NDDs including ASD. GIGYF1 is involved in neurodevelopment and animal behavior, potentially through regulating hippocampal CA2 neuronal numbers and disturbing synaptic transmission.
Biol Psychiatry. 2023 Mar 14:S0006-3223(23)01091-0. doi: 10.1016/j.biopsych.2023.02.993. Online ahead of print.
ABSTRACT
BACKGROUND: Autism spectrum disorder (ASD) 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 the understanding of the pathology of these disorders.
METHODS: We analyzed the exomes generated by the SPARK project and performed a meta-analysis with previous data. We then generated a zebrafish knockout model and three mouse Gigyf1 knockout models to examine the function of GIGYF1 in neurodevelopment and behavior. Finally, we performed whole tissue and single-nuclei transcriptome analysis to explore the molecular and cellular function of GIGYF1.
RESULTS: GIGYF1 variants are significantly associated with various NDD phenotypes including autism, global developmental delay, intellectual disability, sleep disturbance. Loss of GIGYF1 causes similar behavioral effects in zebrafish and mice, including elevated levels of anxiety and reduced social engagements, which is reminiscent of the behavioral deficits in human patients carrying GIGYF1 mutations. 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 nuclei RNAseq. We also identified a series of downstream target genes of GIGYF1 that affects many aspects of the nervous system especially synaptic transmission.
CONCLUSION: De novo variants (DNVs) of GIGYF1 are associated with NDDs including ASD. GIGYF1 is involved in neurodevelopment and animal behavior, potentially through regulating hippocampal CA2 neuronal numbers and disturbing synaptic transmission.
PMID:36924980 | DOI:10.1016/j.biopsych.2023.02.993
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