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

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 frequen...

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Bibliographic Details
Published in:Scientific reports 2017-04, Vol.7 (1), p.46019-46019, Article 46019
Main Authors: Davies, Faith C. J., Hope, Jilly E., McLachlan, Fiona, Nunez, Francis, Doig, Jennifer, Bengani, Hemant, Smith, Colin, Abbott, Catherine M.
Format: Article
Language:English
Subjects:
631/208/366
631/378/2583
Alleles
Animals
Auditory stimuli
Autism
Base Sequence
Body Weight
Cell death
Children
CRISPR
CRISPR-Cas Systems - genetics
Death, Sudden
Elongation
Epilepsy
Gene Editing
Gene Expression Regulation
Genome
Genome editing
Genotype
Humanities and Social Sciences
Mice
Missense mutation
Motor task performance
multidisciplinary
Mutation
Mutation - genetics
Nerve Degeneration - pathology
Neurodegeneration
Neurodevelopmental disorders
Peptide Elongation Factor 1 - genetics
Peptide Elongation Factor 1 - metabolism
Rodents
Science
Seizures
Seizures - genetics
Spinal Cord - pathology
Translation elongation
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep46019