Alternative titles; symbols
HGNC Approved Gene Symbol: MARS2
SNOMEDCT: 1173035001, 784343003;
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38): 2:197,705,369-197,708,395 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | ?Combined oxidative phosphorylation deficiency 25 | 616430 | Autosomal recessive | 3 |
| Spastic ataxia 3, autosomal recessive | 611390 | Autosomal recessive | 3 |
Using primers designed from EST sequences, Spencer et al. (2004) amplified the human mitochondrial methionyl-tRNA synthetase (mtMetRS) gene (MARS2) from HL-60 cDNA. The gene encodes a deduced 593-amino acid protein with an 18-amino acid mitochondrial import signal sequence. The protein shares a high degree of identity with methionyl-tRNA synthetases from other mammals, but is less well conserved with the corresponding enzymes of lower eukaryotes and does not share considerable sequence similarity to the human cytoplasmic MetRS. The human mtMetRS protein and the E. coli homolog share 19% sequence identity. The domain organization of human mtMetRS closely resembles that of the S. cerevisiae and C. albicans mitochondrial MetRSs. Human mtMetRS contains the signature sequences HIGH and KMSKS that are present in all class I synthetases as well as many of the residues that have been proposed to contribute to a universal core in MetRS of all organisms. Unlike many MetRSs, however, it has no zinc-binding site and lacks a C-terminal extension thought to be important in dimerization. Gel filtration studies indicated that human mtMetRS functions as a monomer with an apparent molecular mass of 67 kD.
Using a recombinant human enzyme affinity-purified from E. coli, Spencer et al. (2004) determined the kinetic parameters for mtMetRS aminoacylation. Like several of the characterized mitochondrial aminoacyl RSs, human mtMetRS can aminoacylate the heterologous E. coli tRNA.
Bonnefond et al. (2005) determined that MARS2 is a single-exon gene and spans 1.8 kb.
Gross (2014) mapped the MARS2 gene to chromosome 2q33.1 based on an alignment of the MARS2 sequence (GenBank AB107013) with the genomic sequence (GRCh37).
Spastic Ataxia 3
In 54 patients from 38 French Canadian families with autosomal recessive spastic ataxia-3 (SPAX3; 611390), most of whom were originally reported by Thiffault et al. (2006), Bayat et al. (2012) identified complex duplication rearrangements of the MARS2 gene. Haplotype analysis indicated that 3 duplication events (609728.0001-609728.0003) involving the MARS2 gene had occurred in their SPAX3 cohort. All patients carried these rearrangements in the homozygous or compound heterozygous state, and the rearrangements segregated with the disorders in the families; in addition, a Brazilian patient with a similar phenotype also carried a homozygous duplication. The rearrangements were found using PCR, array CGH, sequencing, and Southern blot analysis. These data suggested that homologies among repeat elements were responsible for complex rearrangements, and Bayat et al. (2012) hypothesized that the numerous repetitive elements present in this gene induced genomic instability and caused template switching during DNA replication, as well as recombination errors. Cultured patient cells showed reduced complex I activity, increased levels of reactive oxygen species, and decreased cell proliferation rates compared to controls. Patient cells had increased levels of MARS2 mRNA, but decreased protein levels. The paradoxical decrease in protein levels may be due to an RNAi-mediated mechanism. Knockdown of MARS2 in HEK293 cells using shRNA caused some decreases in mitochondrial translation, with significant decreases only when protein levels were reduced beyond a certain level. Genotype/phenotype correlation analysis showed that patients with the Dup-Del rearrangement (609728.0001) tended to have an earlier age at onset, as did patients who were homozygous for the Dup1 rearrangement (609728.0002).
Combined Oxidative Phosphorylation Deficiency 25
In 2 sibs with combined oxidative phosphorylation deficiency-25 (COXPD25; 616430), Webb et al. (2015) identified compound heterozygous mutations in the MARS2 gene (609728.0004 and 609728.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV. Muscle biopsy samples were not available.
Bayat et al. (2012) identified a Drosophila strain homozygous for mutations in the Drosophila homolog of the human MARS2 gene. Mutant flies had age-dependent degeneration of photoreceptors in the eye, consistent with defects in neuronal function and survival. Other features of these flies included reduced life span, muscle degeneration with abnormal myofibrils and abnormal mitochondria, and impaired cell proliferation in epithelial tissues. Cellular studies of mutant flies showed defects in oxidative phosphorylation, increased reactive oxygen species, and an upregulation of the mitochondrial unfolded protein response.
In affected members of several French Canadian families with autosomal recessive spastic ataxia-3 (SPAX3; 611390), Bayat et al. (2012) identified a heterozygous 268-bp deletion in the MARS2 gene, resulting in a frameshift and premature termination (c.681del268bpfs236Ter). The deletion was identified using PCR analysis and array comparative genomic hybridization (array CGH), and was determined to be part of a complex partial duplication of the coding region of the MARS2 gene; the allele was termed 'Dup-Del.' All patients carried this specific allele in compound heterozygosity with a different duplication, termed 'Dup1,' affecting the MARS2 gene on the other allele (609728.0002). Copy number variation involving the MARS2 gene was not observed in 384 control individuals. Cells derived from patients carrying the Dup-Del allele showed decreased amounts of wildtype MARS2 compared to controls, but increased levels of the mutant truncated protein compared to the level of wildtype protein found in controls. Patient cells also showed decreased complex I activity and reduced cell proliferation rates compared to wildtype.
In affected members of several French Canadian families with autosomal recessive spastic ataxia-3 (SPAX3; 611390), Bayat et al. (2012) identified a homozygous duplication of the MARS2 gene, termed 'Dup1.' Full genomic sequencing and the identification of breakpoints was hampered by the presence of repetitive sequences at the 5-prime end of the gene and the small size of the gene. Quantitative Southern blot analysis indicated that the breakpoints were over 15 kb away from the wildtype copy of the MARS2 gene. Two copies of MARS2 were detected on each chromosome: the first one contained the entire coding and noncoding sequence, whereas the duplicated copy included only the coding sequence. Affected individuals from several additional families with the disorder were compound heterozygous for Dup1 and a Dup-Del allele (609728.0001) or a different duplication (Dup2; 609728.0003). Copy number variation involving the MARS2 gene was not observed in 384 control individuals. Cells derived from patients carrying a Dup1 allele showed an increase in MARS2 mRNA expression, but a decrease in MARS2 protein, ranging from 40 to 80% of control values. Cells from patients who were homozygous for Dup1/Dup1 showed cellular defects in mitochondrial translation in lymphoblast cell lines; these patients had earlier onset compared to other patients.
In affected members of several French Canadian families with autosomal recessive spastic ataxia-3 (SPAX3; 611390), Bayat et al. (2012) identified a homozygous duplication of the MARS2 gene, termed 'Dup2.' The duplication was similar to Dup1 (609728.0002), but included a small deletion in the 3-prime untranslated region. Copy number variation involving the MARS2 gene was not observed in 384 control individuals. Patients homozygous for the Dup2 allele had a later age at onset compared to other patients.
In 2 sibs with combined oxidative phosphorylation deficiency-25 (COXPD25; 616430), Webb et al. (2015) identified compound heterozygous mutations in the MARS2 gene: a c.550C-T transition (c.550C-T, NM_138395.3), resulting in a gln184-to-ter (Q184X) substitution, and a c.424C-T transition, resulting in an arg142-to-trp (R142W; 609728.0005) substitution at a highly conserved residue. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV that could be rescued by overexpression of wildtype MARS2. Muscle biopsy samples were not available.
For discussion of the c.424C-T transition (c.424C-T, NM_138395.3) in the MARS2 gene, resulting in an arg142-to-trp (R142W) substitution, that was found in compound heterozygous state in 2 sibs with combined oxidative phosphorylation deficiency-25 (COXPD25; 616430) by Webb et al. (2015), see 609728.0004.
Bayat, V., Thiffault, I., Jaiswal, M., Tetreault, M., Donti, T., Sasarman, F., Bernard, G., Demers-Lamarche, J., Dicaire, M.-J., Mathieu, J., Vanasse, M., Bouchard, J.-P., Rioux, M.-F., Lourenco, C. M., Li, Z., Haueter, C., Shoubridge, E. A., Graham, B. H., Brais, B., Bellen, H. J. Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLos Biol. 10: e1001288, 2012. Note: Electronic Article. [PubMed: 22448145] [Full Text: https://doi.org/10.1371/journal.pbio.1001288]
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]
Gross, M. B. Personal Communication. Baltimore, Md. 1/28/2014.
Spencer, A. C., Heck, A., Takeuchi, N., Watanabe, K., Spremulli, L. L. Characterization of the human mitochondrial methionyl-tRNA synthetase. Biochemistry 43: 9743-9754, 2004. [PubMed: 15274629] [Full Text: https://doi.org/10.1021/bi049639w]
Thiffault, I., Rioux, M. F., Tetreault, M., Jarry, J., Loiselle, L., Poirier, J., Gros-Louis, F., Mathieu, J., Vanasse, M., Rouleau, G. A., Bouchard, J. P., Lesage, J., Brais, B. A new autosomal recessive spastic ataxia associated with frequent white matter changes maps to 2q33-34. Brain 129: 2332-2340, 2006. [PubMed: 16672289] [Full Text: https://doi.org/10.1093/brain/awl110]
Webb, B. D., Wheeler, P. G., Hagen, J. J., Cohen, N., Linderman, M. D., Diaz, G. A., Naidich, T. P., Rodenburg, R. J., Houten, S. M., Schadt, E. E. Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. Hum. Mutat. 36: 587-592, 2015. [PubMed: 25754315] [Full Text: https://doi.org/10.1002/humu.22781]