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Is mitochondrial tRNA(phe) variant m.593T>C a synergistically pathogenic mutation in Chinese LHON families with m.11778G>A?

Zhang AM, Bandelt HJ, Jia X, Zhang W, Li S, Yu D, Wang D, Zhuang XY, Zhang Q, Yao YG - PLoS ONE (2011)

Bottom Line: Mitochondrial transfer RNA (mt-tRNA) mutations have been reported to be associated with a variety of diseases.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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.

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.

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Related in: MedlinePlus

Predicted secondary structure of the wild type human MT-TF gene (A) and the mutant harboring m.593T>C (B).Position 593 was marked by an arrow. ΔG means the free energy.
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pone-0026511-g004: Predicted secondary structure of the wild type human MT-TF gene (A) and the mutant harboring m.593T>C (B).Position 593 was marked by an arrow. ΔG means the free energy.

Mentions: The free energy is a criterion for judging the stability of RNA structure in vivo; most of the RNA secondary structure predictions are based on the free energy minimization method [32], [34]. The RNA secondary structure can be predicted more accurately by thermodynamics determined from the primary sequence without information of tertiary contacts or protein interaction; the lower the free energy the more stable the structure is, but this is not an absolute fact because of biological complexity [35]. Alteration of the MT-TF gene secondary structure in the presence of m.593T>C is shown in Figure 4. The predicted structure of the wild type MT-TF gene has a free energy (ΔG) value of −10.94 (Fig. 4A). There are two predicted structures of the MT-TF gene bearing variant m.593T>C. The first type is similar to that of the wild type gene, whereas the second one has a lower free energy value of −11.4 and a reduced size of the dihydrouracil loop (D loop) (Fig. 4B). We speculate that the shift of two predicted structures of the MT-TF gene in vivo in the presence of m.593T>C might slightly impair its function, despite the fact that the second predicted structure had a lower free energy (which means higher stability).


Is mitochondrial tRNA(phe) variant m.593T>C a synergistically pathogenic mutation in Chinese LHON families with m.11778G>A?

Zhang AM, Bandelt HJ, Jia X, Zhang W, Li S, Yu D, Wang D, Zhuang XY, Zhang Q, Yao YG - PLoS ONE (2011)

Predicted secondary structure of the wild type human MT-TF gene (A) and the mutant harboring m.593T>C (B).Position 593 was marked by an arrow. ΔG means the free energy.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198432&req=5

pone-0026511-g004: Predicted secondary structure of the wild type human MT-TF gene (A) and the mutant harboring m.593T>C (B).Position 593 was marked by an arrow. ΔG means the free energy.
Mentions: The free energy is a criterion for judging the stability of RNA structure in vivo; most of the RNA secondary structure predictions are based on the free energy minimization method [32], [34]. The RNA secondary structure can be predicted more accurately by thermodynamics determined from the primary sequence without information of tertiary contacts or protein interaction; the lower the free energy the more stable the structure is, but this is not an absolute fact because of biological complexity [35]. Alteration of the MT-TF gene secondary structure in the presence of m.593T>C is shown in Figure 4. The predicted structure of the wild type MT-TF gene has a free energy (ΔG) value of −10.94 (Fig. 4A). There are two predicted structures of the MT-TF gene bearing variant m.593T>C. The first type is similar to that of the wild type gene, whereas the second one has a lower free energy value of −11.4 and a reduced size of the dihydrouracil loop (D loop) (Fig. 4B). We speculate that the shift of two predicted structures of the MT-TF gene in vivo in the presence of m.593T>C might slightly impair its function, despite the fact that the second predicted structure had a lower free energy (which means higher stability).

Bottom Line: Mitochondrial transfer RNA (mt-tRNA) mutations have been reported to be associated with a variety of diseases.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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.

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.

Show MeSH
Related in: MedlinePlus