Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation

Abstract

The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.

The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations

“…Therefore, the question arises why AARS2 mutations cause two very different subtypes with dissimilar tissue involvement. In 2015, Euro et al 16 gave the elegant explanation for the phenomenon. AARS2 is unique among the human mitochondrial aminoacyl-tRNA synthetases because it contains an editing domain for deacylating mischarged tRNAs in addition to the aminoacylation domain.…”

Expansion of the clinical spectrum associated with AARS2‐related disorders

“…Biallelic pathogenic variants in AARS2 , encoding mitochondrial alanyl‐tRNA synthetase, result in a spectrum of findings, ranging from infantile cardiomyopathy to adult‐onset progressive leukoencephalopathy. Among 11 reported infants with hypertrophic cardiomyopathy and mitochondrial respiratory chain complex deficiency secondary to AARS2 variants, one was stillborn and the remaining 10 died before 1 year of life (Calvo et al, ; Euro et al, ; Götz et al, ; Taylor et al, ). In six individuals, AARS2 variants were the cause of progressive leukoencephalopathy (and ovarian failure in female cases).…”

A homozygous mutation of alanyl‐transfer RNA synthetase 2 in a patient of adult‐onset leukodystrophy: A case report and literature review

“…Deficiency in aminoacyl‐tRNA synthetases is known to contribute to mitochondrial diseases in association with a wide spectrum of clinical phenotypes (Fuchs et al, ; Konovalova & Tyynismaa, ). The AARS2 protein contains an editing and an aminoacylation domain, and mutations site‐specifically change its function in the catalysis of aminoacylation (Euro et al, ).…”

“…Strikingly, no cardiopathy is present in adult‐onset leukodystrophy as suggested in our patient and 15 other reported cases (Table ) (Dallabona et al, ; Hamatani et al, ; Lee et al, ; Lynch et al, ; Szpisjak et al, ). To date, all of the infantile cardiomyopathy exhibit a founder mutation, c. 1774C>T (p. R592W), which is located in the editing domain and severely compromises the aminoacylation activity of AARS2 (Euro et al, ). In comparison, mutations in adult‐onset leukodystrophy include combinations of two missense mutations in the aminoacylation domain, a missense mutation in the aminoacylation domain with a truncating mutation, and other combinations.…”

“…In comparison, mutations in adult‐onset leukodystrophy include combinations of two missense mutations in the aminoacylation domain, a missense mutation in the aminoacylation domain with a truncating mutation, and other combinations. These mutations can be classified into three categories of activity impairment based on structural analyses, that is, loss of function, severely impaired, and moderate impaired (Euro et al, ). The extent of reduced aminoacylation activities may lead to differential phenotypes.…”