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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%) (Pā€Š=ā€Š0.083). 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

Native and denaturing gels showing the migration of RNAs of the wild type MT-TF gene and mutants.Electrophoretic mobility is from top to bottom. The mutant tRNAPhe plasmids with m.583G>A and m.611G>A are gifts from Prof. Michael Ibba's lab and were named as G7A hmt-tRNAPhe and G34A hmt-tRNAPhe in their study [9], respectively.
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pone-0026511-g005: Native and denaturing gels showing the migration of RNAs of the wild type MT-TF gene and mutants.Electrophoretic mobility is from top to bottom. The mutant tRNAPhe plasmids with m.583G>A and m.611G>A are gifts from Prof. Michael Ibba's lab and were named as G7A hmt-tRNAPhe and G34A hmt-tRNAPhe in their study [9], respectively.

Mentions: The electrophoretic mobility of the secondary structure of the wild type and mutant MT-TF genes transcribed in vitro showed that variant m.593T>C affected the migration of mutant tRNAPhe compared to the wild type on the native gel. However, this structure change disappeared when we separated the transcribed RNAs on a denaturing gel (Fig. 5). The observed pattern was in good agreement with the predicted change of the secondary structure of the MT-TF gene in the presence of m.593T>C.


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)

Native and denaturing gels showing the migration of RNAs of the wild type MT-TF gene and mutants.Electrophoretic mobility is from top to bottom. The mutant tRNAPhe plasmids with m.583G>A and m.611G>A are gifts from Prof. Michael Ibba's lab and were named as G7A hmt-tRNAPhe and G34A hmt-tRNAPhe in their study [9], respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026511-g005: Native and denaturing gels showing the migration of RNAs of the wild type MT-TF gene and mutants.Electrophoretic mobility is from top to bottom. The mutant tRNAPhe plasmids with m.583G>A and m.611G>A are gifts from Prof. Michael Ibba's lab and were named as G7A hmt-tRNAPhe and G34A hmt-tRNAPhe in their study [9], respectively.
Mentions: The electrophoretic mobility of the secondary structure of the wild type and mutant MT-TF genes transcribed in vitro showed that variant m.593T>C affected the migration of mutant tRNAPhe compared to the wild type on the native gel. However, this structure change disappeared when we separated the transcribed RNAs on a denaturing gel (Fig. 5). The observed pattern was in good agreement with the predicted change of the secondary structure of the MT-TF gene in the presence of m.593T>C.

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%) (Pā€Š=ā€Š0.083). 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