Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TH
SNOMEDCT: 472316006;
The mitochondrial tRNA for histidine is encoded by nucleotides 12138-12206.
Shin et al. (2000) studied a 60-year-old Japanese man who for 10 years had had manifestations of dilated cardiomyopathy. His mother and younger brother were similarly affected. Endomyocardial biopsy demonstrated marked loss or disruption of sarcomeres and massive accumulation of mitochondria of various sizes. In the tRNA of both brothers, a G-to-A transition was found at position 12192 in the MTTH gene. The mutation was located 2 bp from the 3-prime end of the T-psi-C loop of the tRNA. Because the mutation added an A:T basepair and shortened the loop itself, it was thought to affect mitochondrial function.
Searching for the same mutation, Shin et al. (2000) screened 126 patients with hypertrophic cardiomyopathy, 55 patients with dilated cardiomyopathy, and 168 control subjects without cardiac disease. They identified 4 additional patients with the 12192G-A substitution. One had hypertrophic cardiomyopathy and the mother had cardiomyopathy. The second had asymptomatic hypertrophic cardiomyopathy; the third had dilated cardiomyopathy with frequent premature ventricular contractions; and the fourth had dilated cardiomyopathy with heart failure. No control subjects had the mutation. All 5 subjects with the 12192G-A mutation showed homoplasmy. In addition, they shared an A-to-T substitution at position 16318 in the D-loop, which was not detected in other patients with cardiomyopathy or in subjects without cardiomyopathy. These findings strongly supported the close evolutionary relationship of the 2 mtDNA changes in these patients, as well as a single origin of the 12192G-A mutation. All 5 patients reported by Shin et al. (2000) showed no evidence of neurologic abnormalities or of diabetes.
Mimaki et al. (2003) reported a male patient with cardiomyopathy and Leber hereditary optic neuropathy (LHON; 535000) who had the 12192G-A mutation as well as the 11778G-A mutation in the ND4 gene (516003.0001), which is one of the most common mutations found in LHON patients. Because no case of LHON presenting with cardiomyopathy had previously been reported, the findings suggested that this was an instance of double pathogenic mitochondrial DNA mutations associated either synergistically or concomitantly with 2 different clinical manifestations.
In a male patient with pigmentary retinopathy with visual loss, bilateral sensorineural deafness, muscle hypotrophy, testicular dysfunction, and ataxia, Crimi et al. (2003) identified a heteroplasmic 12183G-A mutation in the MTTH gene. The mutation occurred in a highly conserved region of the T-psi-C stem of the tRNA. The clinical course was progressive, with visual loss beginning at age 7 years, hearing loss at age 11 years, and muscle weakness, ataxia, dysarthria, and testicular dysfunction apparent by age 20 years. Brain imaging showed cerebellar hypotrophy and bilateral basal ganglia calcifications. The patient's sister had retinopathy and sensorineural hypoacusis, whereas their mother had bilateral cataracts and audiometric defects; both also carried the 12183G-A mutation. Crimi et al. (2003) noted that the gradient of clinical severity reflected the degree of mutation heteroplasmy.
In a patient with MELAS syndrome (540000) which progressed to MERRF syndrome (545000), Melone et al. (2004) identified a heteroplasmic 12147G-A transition in the MTTH gene. At age 20 years, the patient experienced sudden migrainous headache and vomiting, followed by left hemiparesis and lateral homonymous hemianopia, consistent with MELAS. Seizures also occurred. At age 25 years, he developed myoclonus and ataxia, suggesting MERRF syndrome. His mother had shown similar stroke-like episodes and had died at age 36 years. Muscle biopsy of the proband showed abnormal mitochondrial proliferation and COX-negative fibers.
Taylor et al. (2004) reported another patient with features consistent with MELAS and MERRF syndromes caused by a heteroplasmic 12147G-A mutation. At age 19 years, the previously healthy patient experienced 3 generalized seizures with left upper limb focal onset and headache. He had left extensor plantar response and developed a mild left hemiparesis the next day. Eight days later, he was found collapsed with fixed dilated pupils, and CT scans showed midline shift and hydrocephalus. He recovered but 3 years later remained fatigued and apathetic with cognitive impairment. He also had right-sided ptosis, bilateral optic atrophy, and abnormal gait. Muscle biopsy showed ragged red fibers with decreased respiratory chain function and an 86% mutant load. The mutation was not detected in the patient's mother or other female relatives, suggesting a de novo event.
In affected members of a large 5-generation Han Chinese family with maternally inherited nonsyndromic adult-onset hearing loss (500008), Yan et al. (2011) identified a heteroplasmic 12201T-C transition in the MTTH gene, affecting the acceptor stem of tRNA-His. The mutation was not found in 342 Han Chinese controls. There was wide variability in age at onset and severity, which correlated with mutation load, but the average age at onset was 29 years. Lymphoblastoid cell lines from 3 mutation carriers showed decreased levels of MTTH mRNA (about 25% of normal) as well as about 50% reduction in mitochondrial translation products compared to controls. Overall oxygen consumption of these cells was about 65% of normal, indicating defective respiration.
Crimi, M., Galbiati, S., Perini, M. P., Bordoni, A., Malferrari, G., Sciacco, M., Biunno, I., Strazzer, S., Moggio, M., Bresolin, N., Comi, G. P. A mitochondrial tRNA(his) gene mutation causing pigmentary retinopathy and neurosensorial deafness. Neurology 60: 1200-1203, 2003. [PubMed: 12682337] [Full Text: https://doi.org/10.1212/01.wnl.0000055865.30580.39]
Melone, M. A. B., Tessa, A., Petrini, S., Lus, G., Sampaolo, S., di Fede, G., Santorelli, F. M., Cotrufo, R. Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype. Arch. Neurol. 61: 269-272, 2004. [PubMed: 14967777] [Full Text: https://doi.org/10.1001/archneur.61.2.269]
Mimaki, M., Ikota, A., Sato, A., Komaki, H., Akanuma, J., Nonaka, I., Goto, Y. A double mutation (G11778A and G12192A) in mitochondrial DNA associated with Leber's hereditary optic neuropathy and cardiomyopathy. J. Hum. Genet. 48: 47-50, 2003. [PubMed: 12560876] [Full Text: https://doi.org/10.1007/s100380300005]
Shin, W. S., Tanaka, M., Suzuki, J., Hemmi, C., Toyo-oka, T. A novel homoplasmic mutation in mtDNA with a single evolutionary origin as a risk factor for cardiomyopathy. Am. J. Hum. Genet. 67: 1617-1620, 2000. [PubMed: 11038324] [Full Text: https://doi.org/10.1086/316896]
Taylor, R. W., Schaefer, A. M., McDonnell, M. T., Petty, R. K. H., Thomas, A. M., Blakely, E. L., Hayes, C. M., McFarland, R., Turnbull, D. M. Catastrophic presentation of mitochondrial disease due to a mutation in the tRNA(his) gene. Neurology 62: 1420-1423, 2004. [PubMed: 15111688] [Full Text: https://doi.org/10.1212/01.wnl.0000120667.77372.46]
Yan, X., Wang, X., Wang, Z., Sun, S., Chen, G., He, Y., Mo, J. Q., Li, R., Jiang, P., Lin, Q., Sun, M., Li, W., Bai, Y., Zhang, J., Zhu, Y., Lu, J., Yan, Q., Li, H., Guan, M.-X. Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNA-His gene. J. Med. Genet. 48: 682-690, 2011. [PubMed: 21931169] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100219]