Face valid phenotypes in a mouse model of the most common mutation in EEF1A2 related neurodevelopmental disorder, E122K

Grant F Marshall, Melissa Fasol, Faith C J Davies, Matthew Le Seelleur, Alejandra Fernandez Alvarez, Cavan Bennett-Ness, Alfredo Gonzalez-Sulser, Catherine M Abbott

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 heterozygotes were not observed to have convulsive seizures, they exhibited frequent electrographic seizures and EEG abnormalities, transient early motor deficits and growth defects. Both E122K homozygotes and Eef1a2-null mice developed progressive motor abnormalities, with E122K homozygotes reaching humane endpoints by P31. The null phenotype is driven by progressive spinal neurodegeneration; however, no signs of neurodegeneration were observed in E122K homozygotes. The E122K protein was 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. Nevertheless, motor abnormalities emerged far earlier in E122K homozygotes than in nulls, suggesting a toxic gain of function and/or a possible dominant-negative effect. This 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.

Original languageEnglish
JournalDisease Models and Mechanisms
Volume17
Issue number6
Early online date5 Jan 2024
DOIs
Publication statusE-pub ahead of print - 5 Jan 2024

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