Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function.

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.

Resolving the Taxonomic Status of Chamelea gallina and C. striatula (Veneridae, Bivalvia): A Combined Molecular Cytogenetic and Phylogenetic Approach.

The striped venus clams Chamelea gallina and C. striatula are commercially important bivalves inhabiting European and North African coastal waters. The taxonomic status of these taxa has been the subject of debate for decades. In order to elucidate this issue, we generated 5S and 28S ribosomal RNA and H3 histone gene probes and mapped them by fluorescent in situ hybridization to the chromosomes of morphologically identified striped venus clams, collected from four geographically distant Atlantic and Mediterranean populations. The nucleotide variation at the three DNA markers, that is, the nuclear internal transcribed spacer 2 (ITS2), the mitochondrial cytochrome c oxidase subunit I (COI), and the large ribosomal subunit rRNA (16S) fragments, was also studied and the resultant phylogenetic trees were evaluated. Striking differences in both the chromosome distribution of these genes and the clustering of the samples on the phylogenetic trees observed provide clear evidence that C. gallina and C. striatula are separated species.