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Researchers investigated how the E122K mutation in the EEF1A2 gene, the most common epilepsy-causing mutation in this gene, affects protein production in neurons. Using mouse models and cell cultures, they found that this mutation does not alter the overall rate of protein synthesis as previously reported, but instead disrupts the translation of specific genes, particularly longer transcripts and those involved in synaptic function. The mutation showed a pattern of slightly reduced expression for a subset of proteins rather than affecting all protein production equally.
Why it matters
These findings challenge previous understanding of how this epilepsy-causing mutation works and suggest that therapeutic approaches should focus on restoring specific affected proteins rather than broadly increasing protein synthesis. Understanding which proteins are specifically affected could lead to more targeted treatments for patients with this mutation who suffer from severe epilepsy and intellectual disability.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.