Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TV
SNOMEDCT: 717052002;
The mitochondrial tRNA for valine is encoded by nucleotides 1602-1670.
Charcot-Marie-Tooth Disease, Axonal
In an affected member of a large multigenerational Venezuelan family with a mitochondrial form of axonal Charcot-Marie-Tooth disease (CMTMA; 500013), Fay et al. (2020) identified a homoplasmic c.1661A-G transition in the MTTV gene, predicted to cause disruption of a base pair in the T-stem loop (590105.0003). The mutation, which was found by next-generation sequencing of mtDNA, was subsequently found in 4 additional family members, including 1 clinically asymptomatic individual, all of whom were homoplasmic for the mutation. These 3 affected individuals also had multiple large mtDNA deletions that were not found in the asymptomatic carrier. Northern blot analysis of muscle derived from the 4 patients showed decreased levels of mt-tRNA(Val) mRNA compared to controls. Patient muscle tissue also showed reduced activities of multiple enzymes in the mitochondrial respiratory chain complex, including I+III and IV. The reduction in enzyme activity was greater in those who were more severely affected. Fay et al. (2020) postulated that the mutation may impair mitochondrial translation or function of the mitoribosome, as well as possibly interfering with axonal transport of mitochondria.
Spastic Paraplegia
Shi et al. (2025) identified homoplasmy for the c.1661A-G transition (590105.0003) in the MTTV gene in 10 family members from 3 generations of a Chinese family with mitochondrial spastic paraplegia (SPGM; 500018). It appeared that the disease process displayed anticipation, with later generations exhibiting earlier age of onset. Shi et al. (2025) found that patients from later generations had a lower mtDNA copy number, suggesting that decreased mtDNA over generations may have contributed to earlier onset of disease.
Tiranti et al. (1998) described a novel heteroplasmic G-to-A transition, affecting the acceptor stem of the mitochondrial tRNA-val gene, in a 48-year-old man who presented with progressive ataxia, seizures, mental deterioration, mild myopathy, and hearing loss. Mutant mtDNA was 67% of total mtDNA in the muscle of the proband and was also present at low levels in the muscle of his healthy mother. It was absent in all of the control DNA samples tested. Analysis of single muscle fibers revealed a significantly greater level of mutant mtDNA in cytochrome c oxidase-negative fibers. Tiranti et al. (1998) concluded that mutations of mtDNA may be responsible for neurologic syndromes that, like the present case, are clinically puzzling, and lack typical 'mitochondrial' clues such as elevated levels of blood lactate, overt defects of the respiratory complexes, and clinically documented maternal inheritance.
Sacconi et al. (2002) described a 37-year-old man who, after childhood, developed a complex clinical picture characterized by hearing loss, migraine, ataxia, seizures, cataracts, retinitis pigmentosa, mental deterioration, and hypothyroidism. MRI revealed diffuse calcification of the basal ganglia and cerebral cortical atrophy. Biochemical analysis showed normal activities of respiratory chain enzymes and citrate synthase. Morphologic examination showed scattered ragged-red fibers and poor or absent cytochrome c oxidase staining in 10% of the fibers. A heteroplasmic 1606G-A transition was found in the MTTV gene. Mutant DNA constituted 70% of the total in the proband's muscle. The mutation was absent in blood samples and urinary sediment from his healthy brother and mother. This second patient with the 1606G-A mutation confirmed both the pathogenicity of the mutation and its association with a characteristic complex neurologic phenotype.
McFarland et al. (2002) reported the case of a 35-year-old woman who had 1 surviving child with mitochondrial Leigh syndrome (MILS; 500017) from 10 pregnancies with 4 unrelated partners. A number of her relatives died in early infancy, including her 3 sibs. She had suffered occasional migraine headaches, and examination demonstrated very mild proximal muscle weakness. In contrast, all of her offspring showed evidence of profound mitochondrial dysfunction. One was delivered by cesarean at 32 weeks' gestation because of deteriorating cardiac function. Despite immediate clinical intervention, the baby died of severe cardiac failure at 21 hours of life. Autopsy showed biventricular hypertrophic cardiomyopathy. Six infants died in the early neonatal period with lacticacidosis, the longest survivor dying 85 hours after birth. Although several changes in mitochondrial DNA were found, McFarland et al. (2002) concluded that a C-to-T transition of nucleotide 1624, present in homoplasmic state in the gene encoding mitochondrial tRNA(Val), was responsible for the findings. The change was expected to affect a basepair in the dihydrouridine loop that is highly conserved in species from yeast to human. A marked, selective reduction of the steady-state level of mitochondrial tRNA(Val) in cardiac and skeletal muscle was found in one of the infants that died neonatally and in skeletal muscle from the mother. These and other data suggested that the 1624C-T mutant was rapidly degraded. The marked difference in phenotype between the mother and her offspring was not explained by this defect; the authors suggested that other factors, such as nuclear-encoded components or epigenetic phenomena, might be involved. Given the severe biochemical defect and the low level of mitochondrial tRNA(Val), what was surprising about this family was not that the children were severely affected but that the mother had survived and had so few clinical problems.
Charcot-Marie-Tooth Disease, Axonal, Mitochondrial
In an affected member of a large multigenerational Venezuelan family with a mitochondrial form of axonal Charcot-Marie-Tooth disease (CMTMA; 500013), Fay et al. (2020) identified a homoplasmic c.1661A-G transition in the MTTV gene, predicted to cause disruption of a base pair in the T-stem loop. The mutation, which was found by next-generation sequencing of mtDNA, was subsequently found in 4 additional family members, including 1 clinically asymptomatic individual, all of whom were homoplasmic for the mutation. These 3 affected individuals also had multiple large mtDNA deletions that were not found in the asymptomatic carrier. Northern blot analysis of muscle derived from the 4 patients showed decreased levels of mt-tRNA(Val) mRNA compared to controls. Patient muscle tissue also showed reduced activities of multiple enzymes in the mitochondrial respiratory chain complex, including I+III and IV. The reduction in enzyme activity was greater in those who were more severely affected. The findings suggested mitochondrial dysfunction as a cause of the disorder.
Spastic Paraplegia, Mitochondrial
In 10 members from 3 generations of a Chinese family with mitochondrial spastic paraplegia (SPGM; 500018), Shi et al. (2025) identified homoplasmy for the c.1661A-G transition in the MTTV gene. The mutation was identified by whole-exome and whole-genome sequencing and segregated with disease.
Fay, A., Garcia, Y., Margeta, M., Maharjan, S., Jurgensen, C., Briceno, J., Garcia, M., Yin, S., Bassaganyas, L., McMahon, T., Hou, Y.-M., Fu, Y.-H., Ptacek, L. J. A mitochondrial tRNA mutation causes axonal CMT in a large Venezuelan family. Ann. Neurol. 88: 830-842, 2020. [PubMed: 32715519] [Full Text: https://doi.org/10.1002/ana.25854]
McFarland, R., Clark, K. M., Morris, A. A. M., Taylor, R. W., Macphail, S., Lightowlers, R. N., Turnbull, D. M. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nature Genet. 30: 145-146, 2002. [PubMed: 11799391] [Full Text: https://doi.org/10.1038/ng819]
Sacconi, S., Salviati, L., Gooch, C., Bonilla, E., Shanske, S., DiMauro, S. Complex neurologic syndrome associated with the G1606A mutation of mitochondrial DNA. Arch. Neurol. 59: 1013-1015, 2002. [PubMed: 12056939] [Full Text: https://doi.org/10.1001/archneur.59.6.1013]
Shi, Y., Xie, J., Jiang, J., Yan, X., Chen, X., Hong, S., Liu, J., Xu, G., Su, H., Chen, W., Wang, N., Lin, X. A homoplasmic MT-TV mutation associated with mitochondrial inheritance of hereditary spastic paraplegia. Mov. Disord. 40: 168-173, 2025. [PubMed: 39468830] [Full Text: https://doi.org/10.1002/mds.30048]
Tiranti, V., D'Agruma, L., Pareyson, D., Mora, M., Carrara, F., Zelante, L., Gasparini, P., Zeviani, M. A novel mutation in the mitochondrial tRNA-val gene associated with a complex neurological presentation. Ann. Neurol. 43: 98-101, 1998. [PubMed: 9450773] [Full Text: https://doi.org/10.1002/ana.410430116]