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.
Keywords
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Article info
Publication history
Accepted:
February 16,
2023
Received in revised form:
February 1,
2023
Received:
June 3,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
