Abstract
Mitochondrial transfer RNA (mt-tRNA) mutations have been reported to be associated with a variety of diseases. In a previous paper that studied the mtDNA background effect on clinical expression of Leber's hereditary optic neuropathy (LHON) in 182 Chinese families with m.11778G>A, we found a strikingly high frequency (7/182) of m.593T>C in the mitochondrially encoded tRNA phenylalanine (MT-TF) gene in unrelated LHON patients. To determine the potential role of m.593T>C in LHON, we compared the frequency of this variant in 479 LHON patients with m.11778G>A, 843 patients with clinical features of LHON but without the three known primary mutations, and 2374 Han Chinese from the general populations. The frequency of m.593T>C was higher in LHON patients (14/479) than in suspected LHON subjects (12/843) or in general controls (49/2374), but the difference was not statistically significant. The overall penetrance of LHON in families with both m.11778G>A and m.593T>C (44.6%) was also substantially higher than that of families with only m.11778G>A (32.9%) (P = 0.083). Secondary structure prediction of the MT-TF gene with the wild type or m.593T>C showed that this nucleotide change decreases the free energy. Electrophoretic mobility of the MT-TF genes with the wild type or m.593T>C transcribed in vitro further confirmed the change of secondary structure in the presence of this variant. Although our results could suggest a modest synergistic effect of variant m.593T>C on the LHON causing mutation m.11778G>A, the lack of statistical significance probably due to the relatively small sample size analyzed, makes necessary more studies to confirm this effect.
Highlights
Leber’s hereditary optic neuropathy (LHON; MIM 535000) is characterized by acute or sub-acute visual failure in young adults and is the first mitochondrial disorder described [1,2]
Mitochondrial tRNAs played an important role in mtDNA translation because the nuclear tRNA could not be transported from cytoplasm into mitochondria in human [3,36]
Many pathogenic mutations in Mitochondrial transfer RNA (mt-tRNA) genes have been reported to be associated with human diseases, despite that defining the pathogenicity of mttRNA mutations are not easy [4,5,8,10,37]
Summary
Leber’s hereditary optic neuropathy (LHON; MIM 535000) is characterized by acute or sub-acute visual failure in young adults and is the first mitochondrial disorder described [1,2]. MtDNA background/ haplogroups, and environmental factors have been shown or suggested to affect the penetrance of LHON [1,2]. Human mitochondrial transfer RNAs (mt-tRNAs) are essential for translation of the thirteen mtDNA encoded protein subunits. Mutations in mt-tRNAs, either in a sporadic status or maternally inherited, constitute the most common mtDNA alterations that are associated with human disorders [4]. M.3243A.G in the MT-TL1 [mitochondrially encoded tRNA leucine 1 (UUA/G)] gene is one of the most common mt-tRNA mutations that cause a variety of human diseases, such as diabetes, mitochondrial myopathy, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) [6,7]. Mutations in mt-tRNAs affect biogenesis and function of mt-tRNAs via a large variety of mechanisms, including transcription, maturation, posttranscriptional modification, structure, stability, aminoacylation, capability of binding to elongation factor EF-Tu, and codon reading [10]
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