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

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, nonsense, and frameshift alleles cause recessive multi-system disorders that differentially affect tissues depending on which ARS is mutated. Second, missense alleles cause dominant peripheral neuropathy. 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 tissuepredominant phenotypes. Here, we review our current understanding of ARS-associated disease phenotypes and explore potential explanations for the observed tissue specificity.

Neuropathy‐associated histidyl‐tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafish

“…These observations suggest that a dominant‐negative mechanism may account for ARS‐CMT pathology [53,58]. Among the criteria for a dominant‐negative effect are that (a) the protein typically functions as a dimer; (b) the mutated allele produces a protein that is expressed and is stable; (c) the mutated protein has reduced function; (d) the mutation(s) do not block the ability of the protein to form heterodimers with wild‐type; and (e) the resulting wild‐type mutant heterodimer has reduced function [53].…”

“…Neurological diseases caused by mutations in cytoplasmic ARS genes can be divided into two broad groups, dominantly inherited peripheral neuropathies and recessively inherited developmental encephalopathies [8,11,16]. The recessive genotypes typically cause drastic reductions in ARS levels and/or activity [54][55][56][57], leading to the general consensus that this group of diseases is associated with loss of aminoacylation function [8,58]. By contrast, the relationship between aminoacylation and the dominantly inherited peripheral neuropathies is less clear.…”

Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

“…Despite our patient’s severe clinical presentation and the clear deficit in fibroblast mitochondrial function, these discrepancies between muscle and fibroblast findings are not uncommon in nuclear-encoded gene-associated disorders [ 23 ]. Importantly, the various ARS2 gene defects are notoriously variable when it comes to issue-specific biochemical phenotypes [ 40 ].…”

A Novel Homozygous Missense Mutation in the YARS Gene: Expanding the Phenotype of YARS Multisystem Disease

“…Recently, many diseases have been associated with specific mutations of aminoacyl-tRNA synthetases. In fact, 34 of the 37 genes that encode ARSs, including the YARS gene, have been implicated in early-onset, multisystem, recessive disease [ 5 , 6 ]. Nowaczyk et al described 2 siblings with compound heterozygosity in YARS catalytic and C-terminal domains.…”