Alternative titles; symbols
HGNC Approved Gene Symbol: AARS2
SNOMEDCT: 733600007;
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38) : 6:44,298,731-44,313,347 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | Combined oxidative phosphorylation deficiency 8 | 614096 | Autosomal recessive | 3 |
| Leukoencephalopathy, progressive, with ovarian failure | 615889 | Autosomal recessive | 3 |
The AARS2 gene encodes mitochondrial alanyl-tRNA synthetase, which is responsible for the charging of tRNA-ala with alanine during mitochondrial translation (summary by Gotz et al., 2011).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1999) cloned AARS2, which they designated KIAA1270. The mRNA contains repetitive elements in its 3-prime end, and the deduced 986-amino acid protein shares 46% identity with human AARS (601065). RT-PCR ELISA showed moderate to high expression of AARS2 in all adult and fetal tissues examined, with highest expression in ovary. Expression was high in all adult brain regions examined.
By searching a database for tRNA synthetases, Bonnefond et al. (2005) identified AARS2, which they called MT-ALARS. The deduced 985-amino acid protein has a 68-amino acid mitochondrial targeting signal, resulting in a mature protein of 917 amino acids. AARS2 is a class II amino acid tRNA synthetase, with a C-terminal active-site domain linked to an N-terminal anticodon-binding domain by a short hinge.
Bonnefond et al. (2005) determined that the AARS2 gene contains 22 exons and spans 13.7 kb.
By radiation hybrid analysis, Nagase et al. (1999) mapped the AARS2 gene to chromosome 6.
Combined Oxidative Phosphorylation Deficiency 8
By exome sequencing, Gotz et al. (2011) identified a homozygous mutation in the AARS2 gene (R592W; 612035.0001) in a Finnish girl with combined oxidative phosphorylation deficiency-8 (COXPD8; 614096) manifest as fatal infantile hypertrophic mitochondrial cardiomyopathy and death at age 10 months. An second unrelated Finnish female infant with a more severe mitochondrial cardiomyopathy resulting in death at age 3 days was found to be compound heterozygous for the R592W mutation and a second mutation (612035.0002). The mutations affected the editing and catalytic aminoacylation domains, respectively. Both patients had near-total deficiency of respiratory complexes I, III, and IV in heart tissue, with less severe defects in brain and skeletal muscle; the liver was not affected.
In 5 unrelated patients of European descent with COXPD8 manifest as fatal infantile cardiomyopathy, Taylor et al. (2014) identified homozygous or compound heterozygous mutations in the AARS2 gene (see, e.g., 612035.0001 and 612035.0003). All of the patients carried the R592W mutation on at least 1 allele, and haplotype analysis indicated a founder effect for this mutation. Functional studies of the variants were not performed. The patients were part of a study of 53 patients with mitochondrial respiratory chain complex deficiencies who underwent whole-exome sequencing.
Progressive Leukoencephalopathy With Ovarian Failure
In 6 patients with progressive leukoencephalopathy (LKENP; 615889), including 5 women with premature ovarian failure, Dallabona et al. (2014) identified compound heterozygous mutations in the AARS2 gene (see, e.g., 612035.0004-612035.0007). The mutations in the first 2 patients were found by whole-exome sequencing. Direct sequencing of the AARS2 gene identified pathogenic biallelic mutations in 4 of 11 additional patients with leukodystrophy. The patients had a severe neurodegenerative disorder characterized by loss of motor and cognitive skills, with onset in young adulthood. Studies of the yeast homologs of 2 variants (F50C, 612035.0004 and R521X, 612035.0005) showed that they resulted in a complete or partial loss of protein function; functional studies of the other variants were not performed.
In a Finnish girl with combined oxidative phosphorylation deficiency-8 (COXPD8; 614096) manifest as fatal infantile hypertrophic mitochondrial cardiomyopathy, Gotz et al. (2011) identified a homozygous 1774C-T transition in exon 13 of the AARS2 gene, resulting in an arg592-to-trp (R592W) substitution predicted to impair the editing domain, causing mistranslation. This patient died at age 10 months. Each unaffected parent was heterozygous for the mutation. An unrelated Finnish female infant with the disorder was found to be compound heterozygous for the R592W mutation and a 464T-G transversion in exon 3, resulting in a leu155-to-arg (L155R; 612035.0002) substitution affecting the catalytic aminoacylation domain and causing lack of tRNA aminoacylation. She died on day 3 of life. Her parents were heterozygous carriers of the respective mutations. Both mutations affected highly conserved residues and were not found in 400 Finnish control chromosomes. The mutations caused a near-total deficiency of respiratory chain complexes I, III, and IV in the hearts of the patients, resulting in the primary manifestation of hypertrophic cardiomyopathy, although the brain and skeletal muscles also showed milder respiratory chain defects, suggesting a multisystem disorder. The liver was not affected in either patient.
Taylor et al. (2014) identified the R592W mutation (rs138119149) in 5 unrelated patients of European origin with COXPD8 manifest as fatal infantile cardiomyopathy. Two patients were homozygous for the mutation, whereas 3 were compound heterozygous for R592W and another pathogenic mutation (see, e.g., 612035.0003). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. R592W was not found in the 1000 Genomes Project database or in 238 in-house controls, but it was present at very low frequency (0.0002) in the Exome Sequencing Project database. Haplotype analysis indicated a founder effect for R592W.
For discussion of the leu155-to-arg (L155R) mutation in the AARS2 gene that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-8 (COXPD8; 614096) by Gotz et al. (2011), see 612035.0001.
In yeast studies, Dallabona et al. (2014) found that the L155R mutation behaved as a null allele.
In a British girl with combined oxidative phosphorylation deficiency-8 (COXPD8; 614096) manifest as fatal infantile cardiomyopathy, Taylor et al. (2014) identified compound heterozygosity for 2 mutations in the AARS2 gene: a 1-bp insertion (c.647_648insG), resulting in a frameshift and premature termination (Cys218LeufsTer6), and R592W (612035.0001). She died at 3 months of age. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The c.647insG mutation was not present in the Exome Sequencing Project, 1000 Genomes Project, or dbSNP (build 137) databases or in 238 in-house controls.
In a young woman with progressive leukoencephalopathy with ovarian failure (LKENP; 615889), Dallabona et al. (2014) identified compound heterozygous mutations in the AARS2 gene: a c.149T-G transversion in exon 1, resulting in a phe50-to-cys (F50C) substitution at a highly conserved residue in the aminoacylation domain, and a c.1561C-T transition in exon 11, resulting in an arg521-to-ter (R521X; 612035.0005) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and were present at a frequency of less than 0.01% in the Exome Variant Server database. Studies in the yeast ala1 homolog indicated that the truncating mutant failed to restore growth in a functionally incompetent strain, consistent with a loss of function. The missense mutation was similar to wildtype at 28 degrees C, but it resulted in reduced growth at 37 degree C. The findings suggested that the F50C mutation is deleterious only under stress conditions.
For discussion of the arg521-to-ter (R521X) in the AARS2 gene that was found in compound heterozygous state in a patient with progressive leukoencephalopathy with ovarian failure (LKENP; 615889) by Dallabona et al. (2014), see 612035.0004.
In a man with progressive leukoencephalopathy (LKENP; 615889), Dallabona et al. (2014) identified compound heterozygous mutations in the AARS2 gene: a c.2893G-A transition, resulting in a gly965-to-arg (G965R) substitution, and a c.1213G-A transition, resulting in a glu405-to-lys (E405K; 612035.0007) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and were present at a frequency of less than 0.01% in the Exome Variant Server database. Functional studies of the variant were not performed.
For discussion of the glu405-to-lys (E405K) mutation in the AARS2 gene that was found in compound heterozygous state in a patient with progressive leukoencephalopathy (LKENP; 615889) by Dallabona et al. (2014), see 612035.0006.
Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry 44: 4805-4816, 2005. [PubMed: 15779907] [Full Text: https://doi.org/10.1021/bi047527z]
Dallabona, C., Diodato, D., Kevelam, S. H., Haack, T. B., Wong, L.-J., Salomons, G. S., Baruffini, E., Melchionda, L., Mariotti, C., Strom, T. M., Meitinger, T., Prokisch, H., and 16 others. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82: 2063-2071, 2014. [PubMed: 24808023] [Full Text: https://doi.org/10.1212/WNL.0000000000000497]
Gotz, A., Tyynismaa, H., Euro, L., Ellonen, P., Hyotylainen, T., Ojala, T., Hamalainen, R. H., Tommiska, J., Raivio, T., Oresic, M., Karikoski, R., Tammela, O., Simola, K. O., Paetau, A., Tyni, T., Suomalainen, A. Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am. J. Hum. Genet. 88: 635-642, 2011. [PubMed: 21549344] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.006]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Taylor, R. W., Pyle, A., Griffin, H., Blakely, E. L., Duff, J., He, L., Smertenko, T., Alston, C. L., Neeve, V. C., Best, A., Yarham, J. W., Kirschner, J., and 17 others. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA 312: 68-77, 2014. [PubMed: 25058219] [Full Text: https://doi.org/10.1001/jama.2014.7184]