"Examining the role of aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease"
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that supply the translation machinery with tRNA bound to cognate amino acids. Mutations in glycyl- (GARS), tyrosyl-(YARS), alanyl-(AARS), and histidyl-tRNA synthetase (HARS) have been implicated in dominant Charcot-Marie-Tooth (CMT) disease, a class of late onset, neurodegenerative phenotypes characterized by impaired motor and sensory function in the distal extremities. The identified mutations in these four genes show impaired enzyme function in biochemical and yeast complementation assays, as well as dominant toxicity to axons when overexpressed in C. elegans. Currently, the molecular pathology of ARS mutations associated with CMT disease is unknown; however, multiple mechanisms have been proposed.
Here, we present an overview of the two primary hypotheses for the molecular pathology of ARS-mediated CMT disease: a loss-of-function mechanism caused by antimorphic alleles, and a gain-of-function mechanism caused by neomorphic alleles. We also discuss a method of testing the loss-of-function hypothesis, our current progress, and our future strategies for understanding the cellular effects of ARS mutations and the role they play in human disease.