The GarsP278KY mouse was generated at Jackson several years ago, and was characterized by the Burgess lab at that time. This mouse contains a dominant mutation in the ubiquitously expressed housekeeping gene, glycyl tRNA synthetase (Gars). At the time the mouse was generated, it was already known that dominant mutations in human GARS resulted in Charcot-Marie-Tooth Type 2D (CMT2D) peripheral neuropathy. GarsP278KY represented the first mouse model of CMT2D. The mouse presents normally at birth, but by 2-3 weeks of age shows reduced body weight and muscle strength, neuromuscular junction dysfunction, peripheral axon degeneration, and reduced nerve conduction velocity, among other neurodegenerative phenotypes.
Studies by the Burgess lab and others have revealed that in the mouse, the mutation confers a toxic gain-of-function to the GARS protein. The data set your class is working with was generated to work towards revealing that gain of function. The data is RNA sequencing from whole spinal cord of 3 mutant and 3 wild-type mice of both sexes (12 total samples) at a post-disease onset time point (8 weeks of age). We are specifically using this transcriptional data as a comparison against translational data we are generating using another technique called ribosome-tagging. As Charlie mentioned, at this point we believe the gain-of-function mechanism leads to impairments in translation, but exactly how that happens is still unclear. These data are giving us some clues, and we are currently following up on mitochondrial dysfunction and amino acid deprivation as possible leads.
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