Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease

Abstract

Aminoacyl-tRNA synthetases (ARSs) are responsible for charging amino acids to cognate tRNA molecules, which is the essential first step of protein translation. Interestingly, mutations in genes encoding ARS enzymes have been implicated in a broad spectrum of human inherited diseases. Bi-allelic mutations in ARSs typically cause severe, early-onset, recessive diseases that affect a wide range of tissues. The vast majority of these mutations show loss-of-function effects and impair protein translation. However, it is not clear how a subset cause tissue-specific phenotypes. In contrast, dominant ARS-mediated diseases specifically affect the peripheral nervous system-most commonly causing axonal peripheral neuropathy-and usually manifest later in life. These neuropathies are linked to heterozygosity for missense mutations in five ARS genes, which points to a shared mechanism of disease. However, it is not clear if a loss-of-function mechanism or a toxic gain-of-function mechanism is responsible for ARS-mediated neuropathy, or if a combination of these mechanisms operate on a mutation-specific basis. Here, we review our current understanding of recessive and dominant ARS-mediated disease. We also propose future directions for defining the molecular mechanisms of ARS mutations toward designing therapies for affected patient populations.

Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease

“…A detailed comparison of the phenotype of our cohort of patients, the recently described patients and other ARS‐associated recessive diseases (Meyer‐Schuman & Antonellis, ), revealed a significant overlap. Our cohort of patients had a milder course of the disease but eventually manifested the common features seen in this group of conditions.…”

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…In contrast, other CMT-linked mutations have been reported to cause a loss of charging activity, suggesting that haploinsufficiency of the enzyme may be a possible contributing factor (Griffin et al, 2014; McLaughlin et al, 2012). Supporting this hypothesis, recessive mutations in synthetases have been linked to neurodegenerative disease, as well as many multisystem disorders involving a wider range of tissues, and many of these mutations have been found to reduce aminoacylation activity in vitro (Kodera et al, 2015; McLaughlin et al, 2010; van Meel et al, 2013; Meyer-Schuman and Antonellis, 2017; Nakayama et al, 2017; Puffenberger et al, 2012; Simons et al, 2015; Taft et al, 2013; Wolf et al, 2014; Zhang et al, 2014a). Impaired synthetase function may reduce the amount of charged tRNA available for translation elongation, with a possible increase in the levels of uncharged tRNA.…”

“…Aminoacyl tRNA synthetases catalyze the reaction in which an amino acid is covalently attached to a tRNA with a specific anticodon, resulting in a charged or aminoacyl tRNA. Dominant missense mutations in a large number of cytoplasmic tRNA synthetases have been linked to Charcot-Marie-Tooth disease (CMT; Abbott et al, 2014; Meyer-Schuman and Antonellis, 2017; Park et al, 2008; Stum et al, 2011). However, the underlying molecular mechanism of these disorders has remained elusive.…”

The role of tRNA synthetases in neurological and neuromuscular disorders

“…Pathogenic variants of mt‐ARSs show a variety of phenotypes involving tissues with high energy demand. Despite their crucial housekeeping function and ubiquitous expression, mutations in mt‐ARSs have been implicated in a variety of paediatric and adult onset human neurological disorders of the brain, spinal cord and motor neurons in addition to disorders predominantly affecting other tissues manifesting as cardiomyopathy, myopathy, sensorineural hearing loss and endocrine symptoms . A large number of autosomal recessive disorders specifically affect the brain, and result in lesions of certain neuronal cell types.…”

“…Aminoacyl‐tRNA synthetase proteins (ARS) are a family of nuclear‐encoded enzymes that ensure correct translation of the genetic code by conjugating each of the 20 amino acids to their cognate tRNA molecule . This aminoacylation reaction provides the substrate for the protein translation process.…”