Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TE
SNOMEDCT: 237619009;
The mitochondrial tRNA for glutamic acid is encoded by nucleotides 14674-14742 of the L-strand.
In a 29-year-old man with adult-onset progressive muscle weakness with exercise intolerance and diabetes mellitus (500002), Hao et al. (1995) identified a 14709T-C transition in the MTTE gene, which altered an evolutionarily conserved nucleotide in the region specifying for the anticodon loop of mitochondrial tRNA (glu). The 14709T-C mutation was heteroplasmic, but present at very high levels in the patient's muscle, white blood cells, and hair follicles; lower proportions of mutated mtDNA were observed in white blood cells and hair follicles of all examined maternal relatives.
Hanna et al. (1995) reported a family in which the 14709T-C mutation had different phenotypic associations, including congenital myopathy, mental retardation, cerebellar ataxia, and diabetes mellitus.
In an extensively studied family with myopathy and diabetes mellitus originally reported by Hudgson et al. (1972), McFarland et al. (2004) identified the 14709T-C mutation. The mutation was homoplasmic in almost all tissues from the most severely affected patient and in the muscle tissue from another affected family member. Other members had high percentages of heteroplasmy (80 to 94% mutant load). One asymptomatic family member was homoplasmic for the mutation in white blood cells.
Vialettes et al. (1997) identified the 14709T-C mutation in a proband with adult-onset IDDM and severe myopathy. The patient was also found to have a subclinical hearing impairment of high frequencies, suggesting maternally inherited diabetes and deafness (MIDD; 520000). Mild retinal pigmentary epithelial changes were also detected. In 1 branch of the family, however, the mutation was transmitted through 3 generations without clinical expression of diabetes, retinopathy, deafness, or myopathy. Perucca-Lostanlen et al. (2002) performed in vitro studies of the 14709T-C mutation derived from the patient reported by Vialettes et al. (1997). A subtle decrease in steady-state levels of the mRNA transcripts was detected, but there was no difference in mitochondrial respiratory chain enzymatic activities compared to wildtype. Perucca-Lostanlen et al. (2002) suggested that additional nuclear factors may be involved in expression of the phenotype.
Damore et al. (1999) identified the 14709T-C mutation in a mother and son with mitochondrial myopathy and diabetes mellitus. The case was unusual in that the son had early onset of diabetes mellitus at age 8 years, whereas the mother was diagnosed at age 25 years.
Rigoli et al. (2001) reported a family with the 14709T-C mutation in which affected members had a variable phenotype, including MIDD, diabetes, deafness, and myopathy. Age at onset varied, but 3 patients had onset of symptoms in childhood.
In 17 affected individuals from 12 families with transient infantile mitochondrial myopathy (500009), Horvath et al. (2009) identified a homoplasmic 14674T-C transition in the MTTE gene. The mutation occurred at a poorly conserved nucleotide in the last base at the 3-prime end of the molecule, affecting the discriminator base where the amino acid is attached to the molecule. The mutation was believed to impair mitochondrial translation, as reflected by the ragged-red fibers and COX-negative fibers in patient skeletal muscle. All patients presented at birth or in early infancy with severe hypotonia and muscle weakness, often requiring mechanical ventilation and tube feeding, and all children showed spontaneous recovery between age 4 and 20 months. Some had residual muscle weakness, but no nervous system abnormalities. Clinical improvement correlated with improvements in skeletal muscle biopsies and COX activity. Several unaffected family members carried the mutation, indicating incomplete penetrance. Horvath et al. (2009) suggested that tissue-specific, developmentally timed processes may play a role both in the age-dependent expression and in the reversibility of this disorder. The mutation was not found in 200 German controls and occurred on different haplotypes, indicating multiple independent mutation events.
Mimaki et al. (2010) identified a homoplasmic 14674T-C mutation in 6 Japanese patients with infantile mitochondrial myopathy due to reversible COX deficiency. Studies of cybrids with the 14674T-C mutation showed decreased activities of complexes I, III, and IV. Two additional Japanese patients with the same disorder had a mutation affecting the same nucleotide (14674T-G; 590025.0003).
Uusimaa et al. (2011) reported 5 patients from 4 families with transient acute infantile mitochondrial myopathy and lactic acidosis who were homoplasmic for the 14674T-C mutation. Age at presentation ranged from birth to 4 months, but all had subtle symptoms of hypotonia and feeding difficulties from birth. Two patients also had transient cardiac impairment, 2 had respiratory impairment, and 2 had eye muscle weakness. Only 1 had hepatomegaly. All recovered over months or years, but all showed delayed walking and had persistent muscle weakness, fatigability, or myalgia. Facial weakness, ptosis, and a myopathic facial appearance became more prominent with age. In 2 families, the mother of the index case had mild to moderate myopathic features without the typical infantile presentation. Two patients and the mother of a patient developed hypothyroidism. Muscle biopsies showed ragged-red fibers, increased glycogen and lipids, decreased COX activity, and deficiency of other mitochondrial respiratory enzymes, which improved with age.
In 2 Japanese patients with transient infantile mitochondrial myopathy (500009), Mimaki et al. (2010) identified a homoplasmic 14674T-G transversion in the MTTE gene. Six additional Japanese patients with the same disorder had the 14674T-C mutation (590025.0002) affecting the same nucleotide.
In 3 unrelated Han Chinese families with maternally inherited diabetes and deafness (MIDD; 520000), Wang et al. (2016) identified a homoplasmic 14692A-G mutation in the tRNA(glu) gene. The mutation affected a highly conserved uridine at position 55 in the T-loop of tRNA(glu). This uridine is modified to pseudouridine to form a tertiary basepair with A18 in the D-loop and stabilizes the L-shaped tRNA structure for interaction with components of the translation machinery. Using lymphoblastoid cell lines from patient cells, Wang et al. (2016) showed that the 14692A-G mutation and loss of U55 pseudouridine modification perturbed tRNA(glu) tertiary structure and increased angiogenin (ANG; 105850)-mediated endonucleolytic degradation of tRNA(glu). Failure of tRNA(glu) metabolism caused mild mitochondrial dysfunction that included impaired mitochondrial translation and respiration, reduced mitochondrial membrane potential and ATP production, and elevated production of reactive oxidative species. Deafness and diabetes in the 3 affected families showed late onset and incomplete penetrance. Of the 23 matrilineal relatives in the 3 affected families, 3 exhibited only deafness, 4 exhibited only diabetes, 5 exhibited both deafness and diabetes, and 11 had no clinical phenotype.
Damore, M. E., Speiser, P. W., Slonim, A. E., New, M. I., Shanske, S., Xia, W., Santorelli, F. M., DiMauro, S. Early onset of diabetes mellitus associated with the mitochondrial DNA T14709C point mutation: patient report and literature review. J. Pediat. Endocr. Metab. 12: 207-213, 1999. [PubMed: 10392369] [Full Text: https://doi.org/10.1515/jpem.1999.12.2.207]
Hanna, M. G., Nelson, I., Sweeney, M. G., Cooper, J. M., Watkins, P. J., Morgan-Hughes, J. A., Harding, A. E. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation. Am. J. Hum. Genet. 56: 1026-1033, 1995. [PubMed: 7726155]
Hao, H., Bonilla, E., Manfredi, G., DiMauro, S., Moraes, C. T. Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. Am. J. Hum. Genet. 56: 1017-1025, 1995. [PubMed: 7726154]
Horvath, R., Kemp, J. P., Tuppen, H. A. L., Hudson, G., Oldfors, A., Marie, S. K. N., Moslemi, A.-R., Servidei, S., Holme, E., Shanske, S., Kollberg, G., Jayakar, P., and 17 others. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 132: 3165-3174, 2009. [PubMed: 19720722] [Full Text: https://doi.org/10.1093/brain/awp221]
Hudgson, P., Bradley, W. G., Jenkinson, M. Familial 'mitochondrial' myopathy: a myopathy associated with disordered oxidative metabolism in muscle fibres. Part I. Clinical, electrophysiological and pathological findings. J. Neurol. Sci. 16: 343-370, 1972. [PubMed: 4114165] [Full Text: https://doi.org/10.1016/0022-510x(72)90197-9]
McFarland, R., Schaefer, A. M., Gardner, J. L., Lynn, S., Hayes, C. M., Barron, M. J., Walker, M., Chinnery, P. F., Taylor, R. W., Turnbull, D. M. Familial myopathy: new insights into the T14709C mitochondrial tRNA mutation. Ann. Neurol. 55: 478-484, 2004. [PubMed: 15048886] [Full Text: https://doi.org/10.1002/ana.20004]
Mimaki, M., Hatakeyama, H., Komaki, H., Yokoyama, M., Arai, H., Kirino, Y., Suzuki, T., Nishino, I., Nonaka, I., Goto, Y. Reversible infantile respiratory chain deficiency: a clinical and molecular study. Ann. Neurol. 68: 845-854, 2010. [PubMed: 21194154] [Full Text: https://doi.org/10.1002/ana.22111]
Perucca-Lostanlen, D., Taylor, R. W., Narbonne, H., Mousson de Camaret, B., Hayes, C. M., Saunieres, A., Paquis-Flucklinger, V., Turnbull, D. M., Vialettes, B., Desnuelle, C. Molecular and functional effects of the T14709C point mutation in the mitochondrial DNA of a patient with maternally inherited diabetes and deafness. Biochim. Biophys. Acta 1588: 210-216, 2002. [PubMed: 12393175] [Full Text: https://doi.org/10.1016/s0925-4439(02)00167-9]
Rigoli, L., Prisco, F., Caruso, R. A., Iafusco, D., Ursomanno, G., Zuccarello, D., Ingenito, N., Rigoli, M., Barberi, I. Association of the T14709C mutation of mitochondrial DNA with maternally inherited diabetes mellitus and/or deafness in an Italian family. (Letter) Diabetic Med. 18: 334-336, 2001. [PubMed: 11437868] [Full Text: https://doi.org/10.1046/j.1464-5491.2001.00429-2.x]
Uusimaa, J., Jungbluth, H., Fratter, C., Crisponi, G., Feng, L., Zeviani, M., Hughes, I., Treacy, E. P., Birks, J., Brown, G. K., Sewry, C. A., McDermott, M., Muntoni, F., Poulton, J. Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. J. Med. Genet. 48: 660-668, 2011. [PubMed: 21931168] [Full Text: https://doi.org/10.1136/jmg.2011.089995]
Vialettes, B. H., Paquis-Flucklinger, V., Pelissier, J. F., Bendahan, D., Narbonne, H., Silvestre-Aillaud, P., Montfort, M. F., Righini-Chossegros, M., Pouget, J., Cozzone, P. J., Desnuelle, C. Phenotypic expression of diabetes secondary to a T14709C mutation of mitochondrial DNA: comparison with MIDD syndrome (A3243G mutation): a case report. Diabetes Care 20: 1731-1737, 1997. [PubMed: 9353617] [Full Text: https://doi.org/10.2337/diacare.20.11.1731]
Wang, M., Liu, H., Zheng, J., Chen, B., Zhou, M., Fan, W., Wang, H., Liang, X., Zhou, X., Eriani, G., Jiang, P., Guan, M.-X. A deafness- and diabetes-associated tRNA mutation causes deficient pseudouridinylation at position 55 in tRNA(Glu) and mitochondrial dysfunction. J. Biol. Chem. 291: 21029-21041, 2016. [PubMed: 27519417] [Full Text: https://doi.org/10.1074/jbc.M116.739482]