Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function
| Autor: | Catherine M. Abbott, Laura Kaminioti-Dumont, Colin Smith, Josephine MacDonald, Faith C. J. Davies, Jilly E Hope, Francis Nunez, Grant F. Marshall, Fiona McLachlan, Owen Dando, Oliver Hardt, Vesa Qarkaxhija, Emma R. Wood |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Mutation
Missense EEF1A2 Haploinsufficiency Biology medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine Neurodevelopmental disorder Peptide Elongation Factor 1 Mutant protein Intellectual Disability Intellectual disability Genetics medicine Missense mutation Animals Humans Genetic Predisposition to Disease Molecular Biology Genetics (clinical) Loss function 030304 developmental biology 0303 health sciences Mutation Homozygote General Medicine medicine.disease Disease Models Animal Neurodevelopmental Disorders Gain of Function Mutation 030217 neurology & neurosurgery |
| Zdroj: | Davies, F C J, Hope, J E, McLachlan, F, Marshall, G F, Kaminioti-Dumont, L, Qarkaxhija, V, Nunez, F, Dando, O, Smith, C, Wood, E, MacDonald, J, Hardt, O & Abbott, C M 2020, ' Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function ', Human Molecular Genetics, vol. 29, no. 10, pp. 1592–1606 . https://doi.org/10.1093/hmg/ddaa042 |
| DOI: | 10.1093/hmg/ddaa042 |
| Popis: | Heterozygous de novo mutations in EEF1A2, encoding the tissue-specific translation elongation factor eEF1A2, have been shown to cause neurodevelopmental disorders including often severe epilepsy and intellectual disability. The mutational profile is unusual; ~50 different missense mutations have been identified but no obvious loss of function mutations, though large heterozygous deletions are known to be compatible with life. A key question is whether the heterozygous missense mutations operate through haploinsufficiency or a gain of function mechanism, an important prerequisite for design of therapeutic strategies. In order both to address this question and to provide a novel model for neurodevelopmental disorders resulting from mutations in EEF1A2, we created a new mouse model of the D252H mutation. This mutation causes the eEF1A2 protein to be expressed at lower levels in brain but higher in muscle in the mice. We compared both heterozygous and homozygous D252H and null mutant mice using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. Although the proteomic analysis pointed to a loss of function for the D252H mutant protein, the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. Mice that are heterozygous for the missense mutation show no behavioural abnormalities but do have sex-specific deficits in body mass and motor function. The phenotyping of our novel mouse lines, together with analysis of molecular modelling and interacting proteins, suggest that the D252H mutation results in a gain of function. |
| Databáze: | OpenAIRE |
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