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Nonsense Mutation in AIMP2 Reduces Protein Expression and Causes a Severe Neurodevelopmental Disorder
Patterson, Pryce
Patterson, Pryce
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Abstract
In mammalian cells, a multi-tRNA synthetase complex containing eight aminoacyl-tRNA synthetases, which catalyze nine different reactions, is thought to make protein synthesis more efficient by keeping components of the translational machinery in close proximity. Aminoacyl tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is one of three non-catalytic components of this complex and is essential for its formation and stability. A homozygous nonsense variant (Y35Ter) of AIMP2 appears in the genotypes of patients with severe neurodevelopmental phenotypes. To determine the effect this variant has on expression at the mRNA and protein level, as well as progression of cells through the cell cycle, patient fibroblasts were studied. Fluorescent microscopy and western blotting, along with puromycin-labeling, cell synchronization, and mRNA analysis, were used to determine the cellular impact of this mutation. Through this study, it was determined that this mutation in AIMP2 causes decreased AIMP2 protein levels and altered mRNA expression. Along with that, the puromycin assay showed a lower rate of protein synthesis in patient fibroblasts when compared to ATCC control cells. There was also a slight decrease in the amount of leucyl-tRNA synthetase (LARS) in patient cells. This protein is a member of the multi-tRNA synthetase complex and the observed decrease could indicate that the protein level of other members of the complex are lower in patient cells. While the cell cycle study did not provide any significant results, this could be due to the fact that fibroblasts were used and not neuronal cells. This study showed that a homozygous nonsense variant (Y35Ter) of AIMP2 impacts expression at the mRNA and protein level while also decreasing protein synthesis. Further research into the specific mechanism behind this mutation is needed in order to possibly develop a treatment option for patients presenting with the resulting symptoms.
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2018-12-31
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Biochemistry