title: Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations.
abstract: Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for charging tRNA with cognate amino acids-the first step in protein synthesis. ARSs are required for protein translation in the cytoplasm and mitochondria of all cells. Surprisingly, mutations in 28 of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data indicate that impaired enzyme function is a robust predictor of the pathogenicity of ARS mutations. However, experimental model systems that distinguish between pathogenic and non-pathogenic ARS variants are required for implicating newly identified ARS mutations in disease. Here, we outline strategies to assist in predicting the pathogenicity of ARS variants and urge cautious evaluation of genetic and functional data prior to linking an ARS mutation to a human disease phenotype.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Oprescu
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, United States; Medical Scientist Training Program, and University of Michigan Medical School, Ann Arbor, MI, United States.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Griffin
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States.
authors.forename: Asim A
authors.initials: AA
authors.lastname: Beg
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States; Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, United States. Electronic address: antonell@umich.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015417:Hereditary Sensory and Motor Neuropathy / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011379:Prognosis
chemical_list: D000604:Amino Acyl-tRNA Synthetases
keywords: Aminoacyl-tRNA synthetases; Charcot-Marie-Tooth (CMT) disease; Functional evaluation of disease-associated mutations; Mendelian disease; Neurodevelopmental disease; Peripheral neuropathy