title: Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice.
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.
authors.affiliation: Centre for Genomic &Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Faith C J
authors.initials: FC
authors.lastname: Davies
authors.affiliation: Centre for Genomic &Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.|Muir Maxwell Epilepsy Centre, University of Edinburgh, 20 Sylvan Place, Edinburgh, EH9 1UW, United Kingdom.
authors.forename: Jilly E
authors.initials: JE
authors.lastname: Hope
authors.affiliation: Centre for Genomic &Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: McLachlan
authors.affiliation: Centre for Genomic &Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Francis
authors.initials: F
authors.lastname: Nunez
authors.affiliation: Centre for Genomic &Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Doig
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Hemant
authors.initials: H
authors.lastname: Bengani
authors.affiliation: Academic Department of Neuropathology, Centre for Clinical Brain Sciences, Chancellor's Building, Little France, Edinburgh, EH16 4SB, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: Centre for Genomic &Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.|Muir Maxwell Epilepsy Centre, University of Edinburgh, 20 Sylvan Place, Edinburgh, EH9 1UW, United Kingdom.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Abbott
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D064113:CRISPR-Cas Systems / Q000235:genetics; D003645:Death, Sudden; D000072669:Gene Editing; D005786:Gene Expression Regulation; D016678:Genome; D005838:Genotype; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000473:pathology; D020648:Peptide Elongation Factor 1 / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology
chemical_list: C503235:Eef1a2 protein, mouse; D020648:Peptide Elongation Factor 1