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Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed throughout the protein in multiple functional domains. In biochemical and cell culture experiments, some mutant forms of GARS have been indistinguishable from wild-type protein, suggesting that these in vitro tests might not adequately assess the aberrant activity responsible for axonal degeneration. Recently, mouse and fly models have offered new insights into the disease mechanism. There are still gaps in our understanding of how mutations in a ubiquitously expressed component of the translation machinery result in axonal neuropathy. Here, we review recent reports, weigh the evidence for and against possible mechanisms and suggest areas of focus for future work.

Original publication

DOI

10.1016/j.tins.2009.11.001

Type

Journal article

Journal

Trends Neurosci

Publication Date

02/2010

Volume

33

Pages

59 - 66

Keywords

Animals, Disease Models, Animal, Glycine-tRNA Ligase, Hereditary Sensory and Motor Neuropathy, Humans, Mitochondrial Diseases, Mutation