Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TI
SNOMEDCT: 83978005;
The mitochondrial tRNA for isoleucine is encoded by nucleotides 4263-4331.
To investigate the potential interference of mutations in MTTI with the primordial function of tRNAs, i.e., their aminoacylation by cognate aminoacyl-tRNA synthetases, Degoul et al. (1998) established a human mitochondrial in vitro aminoacylation system specific for isoleucine. They found that the 4269A-G point mutation (590045.0002), associated with cardiomyopathy, did not affect aminoacylation significantly. On the other hand, the 4317A-G point mutation (590045.0001), reported in a case of fatal infantile cardiomyopathy, induced a small but significant decrease in isoleucylation.
Levinger et al. (2004) pointed out that two-thirds of the more than 150 mutations that had been described in the mitochondrial genome had been found in tRNA genes, which constitute only one-tenth of the mitochondrial genome. Twenty-two tRNAs, 11 mRNAs, and 2 rRNAs are produced from long polycistronic primary transcripts with almost no spacers. Pre-tRNAs thus require precise endonucleolytic excision. Furthermore, the CCA triplet that forms the 3-prime end of all tRNAs is not encoded, but must be synthesized by the CCA-adding enzyme after 3-prime end cleavage. Amino acid attachment to the CCA of mature tRNA is performed by aminoacyl-tRNA synthetases, which, like the preceding processing enzymes, are nuclear-encoded and imported into mitochondria. Levinger et al. (2004) critically reviewed the effectiveness and reliability of evidence obtained from reactions with in vitro transcripts that pathogenesis-associated mutant mitochondrial tRNAs can lead to deficiencies in tRNA 3-prime end metabolism (3-prime end cleavage, CCA addition, and aminoacylation).
Tanaka et al. (1990) identified a 4317A-G mutation in the tRNA-ile gene in a case of fatal infantile cardiomyopathy. The patient was a 1-year-old boy who, in addition to severe dilatation and hypertrophy of the heart, had features of MELAS.
Tomari et al. (2003) demonstrated that the 4317A-G mutation inhibits in vitro CCA addition to the tRNA by the human mitochondrial CCA-adding enzyme. They observed a structural rearrangement of the T-arm region, conferring an aberrantly stable T-arm structure and an increased T(m) value.
Taniike et al. (1992) described a patient with mitochondrial encephalomyopathy who died from progressive intractable cardiac failure at the age of 18 years. He presented at the age of 4 with short stature; multiorgan disorders including deafness, focal glomerulosclerosis, epilepsy, and dilated cardiomyopathy appeared later in his course. Laboratory tests showed hyperlactatemia and hyperpyruvatemia. Histopathologic findings included mitochondrial myopathy with ragged-red fibers and focal cytochrome c oxidase-deficient fibers in skeletal and cardiac muscles. Sequencing demonstrated a novel point mutation: a 4269A-G transition in the tRNA-ile region. The mutation was found in none of the 30 controls.
Merante et al. (1996) identified a 4295A-G transition in the MTTI gene in a 7-month-old girl who had had sudden onset of cyanotic spells and died as a result of complications of hypertrophic cardiomyopathy (see 192600). Despite the hypertrophied left ventricle demonstrated by autopsy, the patient had had no symptoms of cardiac failure, exercise intolerance, or cyanosis until shortly before admission to the hospital, and normal developmental milestones had been achieved. Ultrastructural studies of tissue at autopsy showed massive proliferation of mitochondria in heart and liver but not in skeletal muscle fibers. A brother was found to have concentric left ventricular hypertrophic cardiomyopathy, mild mitral regurgitation, and an ejection fraction of 47% at 2 years of age. Neurologic examination at age 5 was normal, but endocardial biopsy showed mitochondrial hypertrophy. The brother subsequently underwent cardiac transplantation after a sudden deterioration of cardiac function and was 'doing well' 8 months after transplant. Two additional children, aged 6 and 2, demonstrated no cardiac symptoms, but an abnormally elevated blood lactate level was found in one. Again extensive neurologic examinations were normal. The mother, 32 years of age at the time of report, was asymptomatic and her endocardial biopsy showed no mitochondrial hypertrophy. The 4295A-G transition was heteroplasmic in this case. The mutant mitochondrial chromosome was present in approximately 90% in the heart tissue of the proband and the affected brother; the mother had less mutant DNA (approximately 78%), well below the expected expression threshold for the disease. In the proband and other members of the family, the proportion of mutant DNA in different tissues varied widely due to replicative segregation.
In affected members of a 3-generation family with maternally inherited nonsyndromic sensorineural deafness (500008), Gutierrez Cortes et al. (2012) identified a homoplasmic 4295A-G transition in the MTTI gene. Cybrid cell lines carrying the mutation showed a 50% decline in mitochondrial oxygen consumption and a decrease of 37% in complex III activity compared to controls, indicating a defect in mitochondrial respiration. Complex III assembly, as assessed by gel electrophoresis, was also decreased (32% compared to controls), while other complexes were normal. Reduced penetrance was observed.
Corona et al. (2002) reported a family in which the mother and 2 sons were heteroplasmic for a 4284G-A transition in the MTTI gene. The proband showed isolated spastic paraparesis. A brother, who had suffered from a multisystem progressive disorder, ultimately died of cardiomyopathy. Another brother was healthy. The proband's mother showed truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, and diabetes mellitus. A muscle biopsy performed in the proband failed to show the morphologic abnormalities typical of mitochondria disorders; the activities of respiratory chain complexes were normal. However, complex I and IV activities were low in the muscle homogenate of the affected mother and brother. The mutation load was approximately 55%, 80%, and 90% in muscle mtDNA of the proband, his mother, and his affected brother, respectively. The mutation was undetected in the healthy brother. The deceased maternal grandmother had deafness and diabetes and a sister of the mother was deaf.
Limongelli et al. (2004) reported a family in which the mother and 2 daughters were homoplasmic for a 4290T-C transition in the MTTI gene. The proband was in good health until age 16 when she suddenly developed diplopia, headache, vertigo, generalized weakness and malaise, and rapid weight gain. Examination revealed nystagmus as well as impaired glucose tolerance, hyperlipidemia, and hyperuricemia. On MRI she had lesions throughout the deep gray structures of the brain. Her younger sister, who had very similar lesions on MRI, was more severely affected, developing virtually identical neurologic signs and symptoms at age 6, and dying of central respiratory failure at age 21. An older sister of the proband had died unexpectedly at 1 year of age of respiratory arrest after a minor viral infection. The mother was healthy, and muscle biopsies of the mother and 2 daughters showed no ragged-red fibers or cytochrome c oxidase-depleted fibers. Limongelli et al. (2004) concluded that their findings supported the concept that homoplasmic mutations in tRNA genes can cause mitochondrial disorders characterized by incomplete penetrance.
In 2 families with hypertrophic cardiomyopathy (see 192600), Taylor et al. (2003) identified a homoplasmic 4300G-A transition in the MTTI gene. Cardiac tissue from the proband in the presenting family exhibited severe deficiencies of mitochondrial respiratory chain enzymes, whereas histochemical and biochemical studies of skeletal muscle were normal. The mutation was present in all samples from affected individuals and other maternal relatives. Taylor et al. (2003) stated that this was the first report of a homoplasmic mitochondrial tRNA mutation causing maternally inherited hypertrophic cardiomyopathy, and noted that these cases confirm the importance of the MTTI gene as a hotspot for mitochondrial cardiomyopathy mutations.
In a 4-generation pedigree segregating mitochondrial inheritance of hypertension, hypercholesterolemia, and hypomagnesemia (500005), Wilson et al. (2004) identified a C-to-T transition at mitochondrial nucleotide 4291 immediately 5-prime of the tRNA isoleucine anticodon. All individuals in the maternal lineage were homoplasmic for this mutation. Hypomagnesemia, hypertension, and hypercholesterolemia each showed 50% penetrance among adults on the maternal lineage.
Corona, P., Lamantea, E., Greco, M., Carrara, F., Agostino, A., Guidetti, D., Dotti, M. T., Mariotti, C., Zeviani, M. Novel heteroplasmic mtDNA mutation in a family with heterogeneous clinical presentations. Ann. Neurol. 51: 118-122, 2002. [PubMed: 11782991] [Full Text: https://doi.org/10.1002/ana.10059]
Degoul, F., Brule, H., Cepanec, C., Helm, M., Marsac, C., Leroux, J.-P., Giege, R., Florentz, C. Isoleucylation properties of native human mitochondrial tRNA-ile and tRNA-ile transcripts: implications for cardiomyopathy-related point mutations (4269, 4317) in the tRNA-ile gene. Hum. Molec. Genet. 7: 347-354, 1998. [PubMed: 9466989] [Full Text: https://doi.org/10.1093/hmg/7.3.347]
Gutierrez Cortes, N., Pertuiset, C., Dumon, E., Borlin, M., Hebert-Chatelain, E., Pierron, D., Feldmann, D., Jonard, L., Marlin, S., Letellier, T., Rocher, C. Novel mitochondrial DNA mutations responsible for maternally inherited nonsyndromic hearing loss. Hum. Mutat. 33: 681-689, 2012. [PubMed: 22241583] [Full Text: https://doi.org/10.1002/humu.22023]
Levinger, L., Morl, M., Florentz, C. Mitochondrial tRNA 3-prime end metabolism and human disease. Nucleic Acids Res. 32: 5430-5441, 2004. [PubMed: 15477393] [Full Text: https://doi.org/10.1093/nar/gkh884]
Limongelli, A., Schaefer, J., Jackson, S., Invernizzi, F., Kirino, Y., Suzuki, T., Reichmann, H., Zeviani, M. Variable penetrance of a familial progressive necrotising encephalopathy due to a novel tRNA(ile) homoplasmic mutation in the mitochondrial genome. J. Med. Genet. 41: 342-349, 2004. [PubMed: 15121771] [Full Text: https://doi.org/10.1136/jmg.2003.016048]
Merante, F., Myint, T., Tein, I., Benson, L., Robinson, B. H. An additional mitochondrial tRNA-ile point mutation (A-to-G at nucleotide 4295) causing hypertrophic cardiomyopathy. Hum. Mutat. 8: 216-222, 1996. [PubMed: 8889580] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)8:3<216::AID-HUMU4>3.0.CO;2-7]
Tanaka, M., Ino, H., Ohno, K., Hattori, K., Sato, W., Ozawa, T., Tanaka, T., Itoyama, S. Mitochondrial mutation in fatal infantile cardiomyopathy. (Letter) Lancet 336: 1452 only, 1990. [PubMed: 1978914] [Full Text: https://doi.org/10.1016/0140-6736(90)93162-i]
Taniike, M., Fukushima, H., Yanagihara, I., Tsukamoto, H., Tanaka, J., Fujimura, H., Nagai, T., Sano, T., Yamaoka, K., Inui, K., Okada, S. Mitochondrial tRNA-ile mutation in fatal cardiomyopathy. Biochem. Biophys. Res. Commun. 186: 47-53, 1992. [PubMed: 1632786] [Full Text: https://doi.org/10.1016/s0006-291x(05)80773-9]
Taylor, R. W., Giordano, C., Davidson, M. M., d'Amati, G., Bain, H., Hayes, C. M., Leonard, H., Barron, M. J., Casali, C., Santorelli, F. M., Hirano, M., Lightowlers, R. N., DiMauro, S., Turnbull, D. M. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 41: 1786-1796, 2003. [PubMed: 12767666] [Full Text: https://doi.org/10.1016/s0735-1097(03)00300-0]
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]
Wilson, F. H., Hariri, A., Farhi, A., Zhao, H., Petersen, K. F., Toka, H. R., Nelson-Williams, C., Raja, K. M., Kashgarian, M., Shulman, G. I., Scheinman, S. J., Lifton, R. P. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science 306: 1190-1194, 2004. [PubMed: 15498972] [Full Text: https://doi.org/10.1126/science.1102521]