Early onset motor defects and electrographic seizures in a mouse model of the most common mutation in EEF1A2 related neurodevelopmental disorder, E122K
De novo heterozygous missense mutations in EEF1A2, encoding neuromuscular translation-elongation factor eEF1A2, are associated with developmental and epileptic encephalopathies. We used CRISPR/ Cas9 to recapitulate the most common mutation, E122K, in mice. Although E122K/+ mice were not observed to have convulsive seizures, they exhibit frequent electrographic seizures and EEG abnormalities, transient early motor delays and growth defects. Both E122K homozygotes and Eef1a2-null mice develop progressive motor abnormalities phenotypes, with homozygotes reaching humane endpoints by P31. Surprisingly, E122K homozygotes did not exhibit the progressive spinal neurodegeneration which drives the null phenotype. The E122K protein is relatively stable in neurons yet highly unstable in skeletal myocytes, suggesting that the E122K/E122K phenotype is instead driven by loss-of-function in muscle. Importantly, E122K homozygotes developed abnormalities far earlier than nulls, suggesting a toxic gain-of-function. This novel mouse model represents the first animal model of an EEF1A2 missense mutation with face-valid phenotypes and has provided mechanistic insights needed to inform rational treatment design.