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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

Network of 75 mtDNAs with m.593T>C that were identified in 479 LHON patients, 843 suspected LHON patients and 2374 Han Chinese from the general populations.Each circle represents an mtDNA haplotype, with its area being proportional to the frequency of the haplotype. The order of mutations on each uninterrupted branch section is arbitrary. Recurrent mutations are underlined. The length polymorphisms of the C-tracts in regions 16183–16192 and 303–309 and of AC repeats in region 515–524 in the mtDNA control region were disregarded. All individuals contain variants 16519-73-263-315+C-750 relative to the revised Cambridge reference sequence (rCRS) [20]. The current classification within M7b will need some revision in the future in regard to the positions 16189 and 16192, so that the exact number of 593 mutational events is left undetermined for the time being.
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pone-0026511-g003: Network of 75 mtDNAs with m.593T>C that were identified in 479 LHON patients, 843 suspected LHON patients and 2374 Han Chinese from the general populations.Each circle represents an mtDNA haplotype, with its area being proportional to the frequency of the haplotype. The order of mutations on each uninterrupted branch section is arbitrary. Recurrent mutations are underlined. The length polymorphisms of the C-tracts in regions 16183–16192 and 303–309 and of AC repeats in region 515–524 in the mtDNA control region were disregarded. All individuals contain variants 16519-73-263-315+C-750 relative to the revised Cambridge reference sequence (rCRS) [20]. The current classification within M7b will need some revision in the future in regard to the positions 16189 and 16192, so that the exact number of 593 mutational events is left undetermined for the time being.

Mentions: We constructed a network for all the 75 mtDNAs with m.593T>C that were identified from the LHON patients (n = 14), suspected LHON patients (n = 12) and Han Chinese from the general populations (n = 49). It is evident that m.593T>C occurred multiple times in different haplogroups, and it defined haplogroups G1c and B5a1c1 (Fig. 3 and Table S2).


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)

Network of 75 mtDNAs with m.593T>C that were identified in 479 LHON patients, 843 suspected LHON patients and 2374 Han Chinese from the general populations.Each circle represents an mtDNA haplotype, with its area being proportional to the frequency of the haplotype. The order of mutations on each uninterrupted branch section is arbitrary. Recurrent mutations are underlined. The length polymorphisms of the C-tracts in regions 16183–16192 and 303–309 and of AC repeats in region 515–524 in the mtDNA control region were disregarded. All individuals contain variants 16519-73-263-315+C-750 relative to the revised Cambridge reference sequence (rCRS) [20]. The current classification within M7b will need some revision in the future in regard to the positions 16189 and 16192, so that the exact number of 593 mutational events is left undetermined for the time being.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026511-g003: Network of 75 mtDNAs with m.593T>C that were identified in 479 LHON patients, 843 suspected LHON patients and 2374 Han Chinese from the general populations.Each circle represents an mtDNA haplotype, with its area being proportional to the frequency of the haplotype. The order of mutations on each uninterrupted branch section is arbitrary. Recurrent mutations are underlined. The length polymorphisms of the C-tracts in regions 16183–16192 and 303–309 and of AC repeats in region 515–524 in the mtDNA control region were disregarded. All individuals contain variants 16519-73-263-315+C-750 relative to the revised Cambridge reference sequence (rCRS) [20]. The current classification within M7b will need some revision in the future in regard to the positions 16189 and 16192, so that the exact number of 593 mutational events is left undetermined for the time being.
Mentions: We constructed a network for all the 75 mtDNAs with m.593T>C that were identified from the LHON patients (n = 14), suspected LHON patients (n = 12) and Han Chinese from the general populations (n = 49). It is evident that m.593T>C occurred multiple times in different haplogroups, and it defined haplogroups G1c and B5a1c1 (Fig. 3 and Table S2).

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