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Trends Genet. 2020 Feb;36(2):105-117. doi: 10.1016/j.tig.2019.11.007. Epub 2019 Dec 12.

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

Author information

1
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
2
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA. Electronic address: antonell@umich.edu.

Abstract

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.

KEYWORDS:

aminoacyl-tRNA synthetases; developmental delay; peripheral neuropathy; protein translation; recessive disease; tRNA charging

PMID:
31839378
DOI:
10.1016/j.tig.2019.11.007

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