Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TL2
SNOMEDCT: 16851005, 447292006, 472315005;
The mitochondrial tRNA for leucine (CUN) is encoded by nucleotides 12266-12336.
Fu et al. (1996) reported a patient with ragged-red muscle fibers and a constellation of clinical features including chronic progressive external ophthalmoplegia (CPEO), ptosis, pigmentary retinopathy, and sensorineural hearing loss in whom they detected a novel point mutation in the tRNAleu(CUN) gene. Fu et al. (1996) identified a heteroplasmic G-to-A substitution at position 12315 by direct DNA sequencing. They noted that this mutation disrupted basepairing in the T-psi-C stem of tRNAleu(CUN). Quantitative analysis showed that the mtDNAs carrying the mutation constituted 94% of total mtDNA in 2 independent muscle biopsies. Fu et al. (1996) reported that the mutation was not detected in blood samples from the patient or in cultures of fibroblasts. This mutation was not found in samples from 63 independent controls. They established primary myoblast (satellite cell) cultures from the patient and these cultures proved to be homoplasmic wildtype. Fu et al. (1996) suggested that mtDNA carrying the tRNAleu(CUN) mutation at position 12315 accumulated in postmitotic muscle cells but was lost primarily by genetic drift in mitotic cells. They suggested that these results raise the possibility of elimination of the mutant mtDNA genotype from skeletal muscle and restoration of a normal muscle phenotype by regeneration of mature muscle fibers from satellite cells. Fu et al. (1996) noted that the ragged-red fiber appearance is due to the proliferation of mitochondria in muscle fibers and that this may reflect an attempt by the cell to compensate for an imbalance between oxidative ATP supply and demand.
In a patient manifesting an isolated skeletal myopathy, Weber et al. (1997) identified a heteroplasmic A-to-G transition at position 12320 in the MTTL2 gene. The mutation affected the T-psi-C loop at a conserved site and was not found in 120 controls. Analysis of cultured fibroblasts, white blood cells/platelets, and skeletal muscle showed only that skeletal muscle contained the mutation and that only this tissue demonstrated a biochemical defect of respiratory chain activity. In a series of 4 muscle biopsy specimens taken over a 12-year period, there was a gradual increase, from 70 to 90%, in the overall level of the mutation, as well as a marked clinical deterioration. Single-fiber PCR confirmed that the proportion of mutant mtDNA was highest in cytochrome c oxidase-negative fibers.
In a 36-year-old Italian patient with congestive heart failure, Grasso et al. (2001) identified a heteroplasmic 12297T-C mutation in the MTTL2 gene. An endomyocardial biopsy showed wide variation in size and shape of the mitochondria, with several composed of peripheral rings of mitochondrial membranes and devoid of internal cristae. The 12297T-C mutation, which affected a highly conserved nucleotide, was heteroplasmic with a higher amount of mutant DNA in the myocardium (88%) than in blood (70%) and was absent in 150 patients with dilated cardiomyopathy and 120 normal controls. The same mutation had previously been identified in an unrelated Italian family with dilated cardiomyopathy associated with endocardial fibroelastosis (Tessa et al., 1999).
Fu, K., Hartlen, R., Johns, T., Genge, A., Karpati, G., Shoubridge, E. A. A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. Hum. Molec. Genet. 5: 1835-1840, 1996. [PubMed: 8923013] [Full Text: https://doi.org/10.1093/hmg/5.11.1835]
Grasso, M., Diegoli, M., Brega, A., Campana, C., Tavazzi, L., Arbustini, E. The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA-leu(CUN) and is associated with dilated cardiomyopathy. Europ. J. Hum. Genet. 9: 311-315, 2001. [PubMed: 11313776] [Full Text: https://doi.org/10.1038/sj.ejhg.5200622]
Tessa, A., Vilarinho, L., Casali, C., Santorelli, F. M. MtDNA-related idiopathic dilated cardiomyopathy. Europ. J. Hum. Genet. 7: 847-848, 1999. [PubMed: 10602359] [Full Text: https://doi.org/10.1038/sj.ejhg.5200380]
Weber, K., Wilson, J. N., Taylor, L., Brierley, E., Johnson, M. A., Turnbull, D. M., Bindoff, L. A. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am. J. Hum. Genet. 60: 373-380, 1997. [PubMed: 9012410]