title: Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations.
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, 13 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.
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, Michigan; Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Griffin
authors.forename: Reiko
authors.initials: R
authors.lastname: Sakaguchi
authors.forename: David
authors.initials: D
authors.lastname: McGuigan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.forename: Charles
authors.initials: C
authors.lastname: Searby
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Hou
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
mesh_terms: D000595:Amino Acid Sequence; D049148:Aminoacylation; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D006032:Glycine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D021381:Protein Transport; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
chemical_list: D006032:Glycine-tRNA Ligase
keywords: Charcot-Marie-Tooth disease; GARS; aminoacyl-tRNA synthetase; glycyl-tRNA synthetase; peripheral neuropathy