The most common epilepsy-causing mutation in EEF1A2 (E122K) perturbs the translation of specific transcripts but not the rate of global protein synthesis

Authors

Bennett Ness, C., Rizzi, M., Love, H., Balkic, N., Marshall, G., von Kriegsheim, A., Osterweil, E. K., Abbott, C. M.

Abstract

Heterozygous de novo missense mutations in the EEF1A2 gene encoding translation elongation factor eEF1A2 result in neurodevelopmental disorders, typically characterised by early onset epilepsy and intellectual disability (ID). The E122K mutation is the most commonly reported missense mutation and is amongst the more severe in terms of epilepsy and ID. Here we made use of a recently developed mouse model which recapitulates the E122K mutation to examine how mutations in EEF1A2 might disrupt neuronal gene expression. Primary neurons from mutant mice and transfected HEK293T cells were used to examine effects on global protein synthesis. In contrast to previous reports, we were unable to detect a change in global protein synthesis using either of two different assay systems. TRAP-seq and mass spectrometry were then employed to study the effects of the mutation on the translatome and proteome respectively. These analyses revealed perturbation of expression of a subset of genes, with a slight skew towards downregulation, particularly for longer transcripts. Further analysis indicated a down regulation of proteins involved in synaptic function in both the translatomic and proteomic datasets.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 13 Jul 2026.

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