Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TG
SNOMEDCT: 233873004, 26636000, 267044007; ICD9CM: 425.1;
The mitochondrial tRNA for glycine is encoded by nucleotides 9991-10058.
Mutations in the mitochondrial tRNAs are associated with mitochondrial disease in which myopathy associated with ragged-red fibers and hypertrophic cardiomyopathy are common features. Graham et al. (1997) hypothesized that these clinical manifestations may derive from severe defects in oxidative phosphorylation, resulting in marked mitochondrial energy deficiency and a compensatory induction of mitochondrial proliferation. To test the hypothesis, they took advantage of the presence of tissue-specific isoforms of adenine nucleotide translocator (ANT1; 103220). ANT1, acting as a solute carrier, exchanges matrix ATP for cytosolic ADP across the inner mitochondrial membrane, providing mitochondrial energy to the cytosol. Graham et al. (1997) reasoned that if ATP deficiency were the cause of mitochondrial myopathy and cardiomyopathy, inactivation of ANT1 would starve the skeletal muscle and the heart of mitochondrial ATP, resulting in the pathology. They produced 'knockout' mice deficient in the heart/muscle isoform of ANT. Histologic and ultrastructural examination of skeletal muscle from Ant1-null mutants revealed ragged-red muscle fibers and a dramatic proliferation of mitochondria, while examination of the heart revealed cardiac hypertrophy with mitochondrial proliferation. Mutant adults had an elevated resting serum lactate and severe exercise intolerance.
Merante et al. (1994) found heteroplasmy for a T-to-C transition at nucleotide 9997 in the MTTG gene in a family in which multiple members manifested nonobstructive hypertrophic cardiomyopathy. The degree of mtDNA heteroplasmy generally correlated with the severity of the symptoms. The mutation disrupted hydrogen bonding in the region adjacent to the acceptor stem of the tRNA molecule. The thymine residue at position 9997 is highly conserved in mammals, as well as in various vertebrates and invertebrates. A PCR diagnostic test showed that the base change was always present in high proportion in affected family members, was not present in unaffected family members, and was never present in control subjects from various ethnic groups. The degree of heteroplasmy in lymphoblast cultures also correlated with the level of enzyme activity present in complex IV and complexes II and III. The proband was an 8.5-month-old male who presented with fatal ventricular arrhythmia and at autopsy was found to have concentric hypertrophy of the left ventricular cavity without obstruction to left ventricular outflow. Electron microscopy identified pleomorphic mitochondria with abnormal cristae. An 11-year-old brother showed abnormalities on left ventricular endocardial biopsy and had an elevated serum lactate and lactate:pyruvate ratio. Additional clinical review of other family members identified several with clinical and echocardiographic diagnosis of nonobstructive hypertrophic cardiomyopathy. No male transmission of the trait was observed. Other possible maternally transmitted clinical manifestations included chronic bowel immotility and renal disease. Merante et al. (1994) suggested that the cardiac phenotype in this family is more aptly classified as a metabolic cardiomyopathy of hypertrophic type according to the definition of the WHO ISFC task force (1980).
Hypertrophic cardiomyopathy is sometimes caused by other mutations in mitochondrial genes, including the C3303T mutation in the MTTL1 gene (590050.0004).
Nishigaki et al. (2002) reported a 42-year-old woman who presented with a long history of progressive muscle fatigue and myalgia, increased serum lactic acid, and intermittent elevated creatine kinase. Histochemical and biochemical analysis of muscle tissue revealed COX-negative ragged-red fibers (RRF) and COX-negative non-RRF, as well as reduced activities of mitochondrial respiratory chain complexes I, III, and IV. Molecular analysis identified a 10010T-C transition in the MTTG gene, which was not present in 50 controls.
In several sibs from 1 family, Santorelli et al. (1996) identified a 10044A-G mutation in the MTTG gene that appeared to be associated with sudden unexpected death. Tomari et al. (2003) demonstrated that this mutation inhibits in vitro CCA addition to the tRNA by the human mitochondrial CCA-adding enzyme. The mutant tRNA(gly) showed high nuclease sensitivity in both the T and the D loops, suggesting a weakened interaction between the loops. These findings and comparable findings in the 4317A-G mutation in the MTTI gene (590045.0001) were thought to be the first reported instances of inefficient CCA addition as a molecular pathogenesis associated with point mutations in human mitochondrial tRNA genes.
Graham, B. H., Waymire, K. G., Cottrell, B., Trounce, I. A., MacGregor, G. R., Wallace, D. C. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nature Genet. 16: 226-234, 1997. [PubMed: 9207786] [Full Text: https://doi.org/10.1038/ng0797-226]
Merante, F., Tein, I., Benson, L., Robinson, B. H. Maternally inherited hypertrophic cardiomyopathy due to a novel T-to-C transition at nucleotide 9997 in the mitochondrial tRNA-glycine gene. Am. J. Hum. Genet. 55: 437-446, 1994. [PubMed: 8079988]
Nishigaki, Y., Bonilla, E., Shanske, S., Gaskin, D. A., DiMauro, S., Hirano, M. Exercise-induced muscle 'burning,' fatigue, and hyper-CKemia: mtDNA T10010C mutation in tRNA-gly. Neurology 58: 1282-1285, 2002. [PubMed: 11971101] [Full Text: https://doi.org/10.1212/wnl.58.8.1282]
Santorelli, F. M., Schlessel, J. S., Slonim, A. E., DiMauro, S. Novel mutation in the mitochondrial DNA tRNA glycine gene associated with sudden unexpected death. Pediat. Neurol. 15: 145-149, 1996. [PubMed: 8888049] [Full Text: https://doi.org/10.1016/0887-8994(96)00163-4]
Tomari, Y., Hino, N., Nagaike, T., Suzuki, T., Ueda, T. Decreased CCA-addition in human mitochondrial tRNAs bearing a pathogenic A4317G or A10044G mutation. J. Biol. Chem. 278: 16828-16833, 2003. [PubMed: 12621050] [Full Text: https://doi.org/10.1074/jbc.M213216200]
WHO ISFC task force. The report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. Brit. Heart J. 44: 672-673, 1980. [PubMed: 7459150] [Full Text: https://doi.org/10.1136/hrt.44.6.672]