Ubiquitously Expressed Proteins and Restricted Phenotypes: Exploring Cell-Specific Sensitivities to Impaired tRNA Charging

Aminoacyl-tRNA synthetases (ARS) are ubiquitously expressed, essential enzymes that charge tRNA with cognate amino acids. Variants in genes encoding ARS enzymes lead to myriad human inherited diseases. First, missense alleles cause dominant peripheral neuropathy. Second, missense, nonsense, and fram...

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Published in:Trends in genetics 2020-02, Vol.36 (2), p.105-117
Main Authors: Kuo, Molly E., Antonellis, Anthony
Format: Article
Language:English
Subjects:
aminoacyl-tRNA synthetases
developmental delay
peripheral neuropathy
protein translation
recessive disease
tRNA charging
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Summary:Aminoacyl-tRNA synthetases (ARS) are ubiquitously expressed, essential enzymes that charge tRNA with cognate amino acids. Variants in genes encoding ARS enzymes lead to myriad human inherited diseases. First, missense alleles cause dominant peripheral neuropathy. Second, missense, nonsense, and frameshift alleles cause recessive multisystem disorders that differentially affect tissues depending on which ARS is mutated. A preponderance of evidence has shown that both phenotypic classes are associated with loss-of-function alleles, suggesting that tRNA charging plays a central role in disease pathogenesis. However, it is currently unclear how perturbation in the function of these ubiquitously expressed enzymes leads to tissue-specific or tissue-predominant phenotypes. Here, we review our current understanding of ARS-associated disease phenotypes and discuss potential explanations for the observed tissue specificity. Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that ligate amino acids onto cognate tRNA molecules.Variants in loci encoding ARS enzymes have been implicated in myriad dominant and recessive human inherited disease phenotypes.Five of the 37 human ARS loci are associated with dominant peripheral neuropathy with a primarily axonal pathology; the vast majority of the alleles cause a loss-of-function effect.Nearly all 37 human ARS loci are associated with recessive multisystem disorders and every genotype results in severely impaired ARS function.Interestingly, for both dominant and recessive phenotypes, certain tissues are exclusively or more severely affected; the mechanism(s) by which specific tissues are affected is not currently known.Defining the molecular mechanism(s) of ARS-related disease and determining the cell-type sensitivity to impaired ARS function will provide insight into the biology of these essential enzymes and will reveal potential therapeutic targets.
ISSN:0168-9525
DOI:10.1016/j.tig.2019.11.007