Abstract
Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (
GARS
) gene cause CMT2D. GARS is a member of the ubiquitously expressed aminoacyl-tRNA synthetase (ARS) family and is responsible for charging tRNA with glycine. To date, thirteen
GARS
mutations have been identified in patients with CMT disease. While functional studies have revealed loss-of-function characteristics, only four
GARS
mutations have been rigorously studied. Here, we report the functional evaluation of nine CMT-associated
GARS
mutations in tRNA charging, yeast complementation, and subcellular localization assays. Our results demonstrate that impaired function is a common characteristic of CMT-associated
GARS
mutations. Additionally, one mutation previously associated with CMT disease (p.Ser581Leu) does not demonstrate impaired function, was identified in the general population, and failed to segregate with disease in two newly identified families with CMT disease. Thus, we propose that this variant is not a disease-causing mutation. Together, our data indicate that impaired function is a key component of
GARS
-mediated CMT disease and emphasize the need for careful genetic and functional evaluation before implicating a variant in disease onset.
