Relevance to Autism

A rare and potentially damaging de novo missense variant in the EIF4G1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Gonatopoulos-Pournatzis et al., 2020 demonstrated that microexon splicing in eIF4G translation initiation factors, a process involved in regulation of the neuronal proteome and higher order cognitive functions, was disrupted in post-mortem brain tissue from autistic patients; furthermore, mice that were deficient for the Eif4g1 microexon (Eif4g1MIC/MIC) displayed learning and memory deficits, altered synaptic plasticity, and autistic-like social behavior.

Molecular Function

The protein encoded by this gene is a component of the multi-subunit protein complex EIF4F. This complex facilitates the recruitment of mRNA to the ribosome, which is a rate-limiting step during the initiation phase of protein synthesis. The recognition of the mRNA cap and the ATP-dependent unwinding of 5'-terminal secondary structure is catalyzed by factors in this complex. The subunit encoded by this gene is a large scaffolding protein that contains binding sites for other members of the EIF4F complex. A domain at its N-terminus can also interact with the poly(A)-binding protein, which may mediate the circularization of mRNA during translation.

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Model Summary

EIF4G1 microexon-deficient mice display deficits in social approach and social memory in the three-chambered assay, decreased social interaction in the reciprocal interaction test, impaired episodic memory measured by the fear conditioning test, and altered hippocampal synaptic plasticity as measured by LTP. Eif4g1^-/- mice have normal weight, motor coordination, locomotion, habituation, anxiety, aggression, hearing, response to light stimuli, cued fear conditioning. Eif4g1^-/- are born at Mendelian ratios and show no change in gross morphology. Eif4g1^-/- mice have increased expression of critical synaptic proteins, including GluN1.

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