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HGNC Approved Gene Symbol: MT-TN
SNOMEDCT: 67434000;
The mitochondrial tRNA for asparagine is encoded by nucleotides 5657-5729.
Clayton (1993) pointed out that this leucyl-tRNA, 1 of 2 in the mitochondrial genome, is located immediately adjacent to the 3-prime end of the gene for 16S rRNA (MTRNR2; 561010) and the 5-prime end of the gene for the subunit 1 protein of complex I (MTND1; 516000); and that this particular DNA sequence evolved for at least 2 critical and quite different purposes, i.e., to encode this particular tRNA species, and to sponsor transcription termination at the end of the rRNA gene region. A small, 13-nucleotide portion of the tRNA gene is the minimal element necessary to effect termination, and this process occurs by the binding of a 34-kD protein to this target sequence. It appears that when the target sequence is occupied by this protein, it presents a barrier to the transcription machinery, thereby terminating transcription at this site. The high number of mutations that have been recognized in this gene may be related to the fact that it occupies a critical role in transcription termination.
In an African American patient with isolated ophthalmoplegia, Moraes et al. (1993) identified a G-to-A transition at position 5703 of the mitochondrial DNA, located in the anticodon stem of the tRNA-asn gene. The mutation disrupted the first basepair of the anticodon stem, a secondary structure highly conserved throughout evolution. This transition also disrupted a DdeI restriction endonuclease site, allowing for easy detection of the mutation by RFLP analysis of PCR fragments. RFLP analysis of DdeI recognition sites had been used extensively in establishing the origins of human populations. From a total of 818 individuals examined, 64 of whom were of African ancestry, there were no reports of a DdeI polymorphic site at position 5703. In addition, none of 57 patients with mitochondrial disease possessed this alteration. In addition to this disease-producing mutation, the proposita had a large number of polymorphisms consistent with her African ancestry. Most of these were located in evolutionarily nonconserved regions and were considered neutral polymorphisms.
Hao and Moraes (1997) found that expression of the MTTN 5703G-A mutation in human osteosarcoma cells resulted in severe impairment of oxidative phosphorylation and mitochondrial protein synthesis. Gel electrophoresis showed that the mutant tRNA fraction had an altered conformation consistent with a destabilized secondary or tertiary structure, which may result in impaired aminoacylation or increased in vivo tRNA degradation by mitochondrial RNases.
Vives-Bauza et al. (2003) reported a girl with the MTTN 5703G-A mutation and isolated progressive ophthalmoplegia beginning at age 4 years. There was no involvement of other cranial nerves nor signs of cardiac, hepatic, or CNS involvement. Physical examination at age 16 years showed moderate progression of ptosis and ophthalmoplegia as well as marked loss of subcutaneous fat and increasing muscle fatigue. Vives-Bauza et al. (2003) noted the phenotypic similarity to the patient reported by Moraes et al. (1993).
In a patient with progressive ophthalmoplegia, Seibel et al. (1994) identified a 5692A-G transition in the MTTN gene. The mutation is located at the transition of the anticodon loop to the anticodon stem and reduces the number of loop-forming nucleotides from 7 to 5, predicting a limitation in mitochondrial protein synthesis.
In a 13-year-old boy with combined deficiency of mitochondrial complexes I (252010) and IV (220110) and a complex phenotype involving multiple organ systems, Meulemans et al. (2006) identified a 5728A-G transition in the MTTN gene. As a young child, he had failure to thrive, renal failure, and mental retardation. He later developed progressive ataxia, muscle weakness, seizures, and increased serum and CSF lactate. Brain CT scan showed basal ganglia calcifications. Mitochondrial mutation load in the patient's skeletal muscle and fibroblasts was 97% and 50%, respectively.
Clayton, D. A. Heavy traffic at a dual-purpose human mitochondrial tRNA gene. (Editorial) J. Clin. Invest. 92: 2567 only, 1993. [PubMed: 8254013] [Full Text: https://doi.org/10.1172/JCI116869]
Hao, H., Moraes, C. T. A disease-associated G5703A mutation in human mitochondrial DNA causes a conformational change and a marked decrease in steady-state levels of mitochondrial tRNA(Asn). Molec. Cell. Biol. 17: 6831-6837, 1997. [PubMed: 9372914] [Full Text: https://doi.org/10.1128/MCB.17.12.6831]
Meulemans, A., Seneca, S., Lagae, L., Lissens, W., De Paepe, B., Smet, J., Van Coster, R., De Meirleir, L. A novel mitochondrial transfer RNA-Asn mutation causing multiorgan failure. Arch. Neurol. 63: 1194-1198, 2006. [PubMed: 16908752] [Full Text: https://doi.org/10.1001/archneur.63.8.1194]
Moraes, C. T., Ciacci, F., Bonilla, E., Jansen, C., Hirano, M., Rao, N., Lovelace, R. E., Rowland, L. P., Schon, E. A., DiMauro, S. Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis: is the tRNA-leu(UUR) gene an etiologic hot spot? J. Clin. Invest. 92: 2906-2915, 1993. [PubMed: 8254046] [Full Text: https://doi.org/10.1172/JCI116913]
Seibel, P., Lauber, J., Klopstock, T., Marsac, C., Kadenbach, B., Reichmann, H. Chronic progressive external ophthalmoplegia is associated with a novel mutation in the mitochondrial tRNA(Asn) gene. Biochem. Biophys. Res. Commun. 204: 482-489, 1994. [PubMed: 7980504] [Full Text: https://doi.org/10.1006/bbrc.1994.2485]
Vives-Bauza, C., Del Toro, M., Solano, A., Montoya, J., Andreu, A. L., Roig, M. Genotype-phenotype correlation in the 5703G-A mutation in the tRNA-Asn gene of mitochondrial DNA. J. Inherit. Metab. Dis. 26: 507-508, 2003. [PubMed: 14518831] [Full Text: https://doi.org/10.1023/a:1025133629685]