Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice

Faith C J Davies,Fiona Mclachlan,Francis Nunez,Catherine M Abbott,Hemant Bengani,Colin Smith,Jilly E Hope,Jennifer Doig

doi:10.1038/srep46019

Abstract

De novo heterozygous missense mutations in the gene encoding translation elongation factor eEF1A2 have recently been found to give rise to neurodevelopmental disorders. Children with mutations in this gene have developmental delay, epilepsy, intellectual disability and often autism; the most frequently occurring mutation is G70S. It has been known for many years that complete loss of eEF1A2 in mice causes motor neuron degeneration and early death; on the other hand heterozygous null mice are apparently normal. We have used CRISPR/Cas9 gene editing in the mouse to mutate the gene encoding eEF1A2, obtaining a high frequency of biallelic mutations. Whilst many of the resulting founder (F0) mice developed motor neuron degeneration, others displayed phenotypes consistent with a severe neurodevelopmental disorder, including sudden unexplained deaths and audiogenic seizures. The presence of G70S protein was not sufficient to protect mice from neurodegeneration in G70S/− mice, showing that the mutant protein is essentially non-functional.

Highlights

De novo heterozygous missense mutations in the gene encoding translation elongation factor eEF1A2 have recently been found to give rise to neurodevelopmental disorders
We show that the presence of eEF1A2 carrying the G70S mutation is insufficient to prevent neurodegeneration, suggesting that the G70S protein is unable to function normally in protein synthesis
We used CRISPR/Cas[9] genome editing; paired gRNAs that target the Eef1a2 gene in the region of the mutation, a single stranded oligonucleotide repair template containing the mutation, and Cas[9] nickase RNA were injected into single cell mouse embryos

Summary

Introduction

De novo heterozygous missense mutations in the gene encoding translation elongation factor eEF1A2 have recently been found to give rise to neurodevelopmental disorders. Children with mutations in this gene have developmental delay, epilepsy, intellectual disability and often autism; the most frequently occurring mutation is G70S It has been known for many years that complete loss of eEF1A2 in mice causes motor neuron degeneration and early death; on the other hand heterozygous null mice are apparently normal. A spontaneously occurring deletion of eEF1A2 in mice causes early onset neurodegeneration in mice when the mutation is homozygous This mutation, called wasted (gene symbol wst) results in complete ablation of expression of eEF1A2, and homozygous mice die by 28 days at the latest with motor neuron degeneration and concomitant muscle wasting. In almost all cases these individuals have severe epilepsy, many have autism, and all have developmental delay and www.nature.com/scientificreports/

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