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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

Classification tree of 12 complete mtDNA sequences, plus the revised Cambridge reference sequence (rCRS) [20].Six Chinese LHON mtDNAs (including Le953 [FJ198218] [11]) had both m.593T>C and m.11778G>A. Five reported mtDNAs (GQ301863 [24], AF347007 [25], AY255137 [26], EF153821 [27], and AP008571 [28]) harbored m.593T>C. One mtDNA (EF429138 [43]) without either variant was used to define the novel haplogroup C7a2. The length polymorphisms of the C-tracts in region 303–309 were disregarded. The order of mutations on each uninterrupted branch segment is arbitrary. Recurrent mutations are underlined. The synonymous and non-synonymous coding-region variants in the mtDNA sequences are denoted by “/s” and “/ns”, respectively. Variants in the ribosomal RNA genes and tRNA genes are denoted by “/r” and “/t”, respectively.
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pone-0026511-g001: Classification tree of 12 complete mtDNA sequences, plus the revised Cambridge reference sequence (rCRS) [20].Six Chinese LHON mtDNAs (including Le953 [FJ198218] [11]) had both m.593T>C and m.11778G>A. Five reported mtDNAs (GQ301863 [24], AF347007 [25], AY255137 [26], EF153821 [27], and AP008571 [28]) harbored m.593T>C. One mtDNA (EF429138 [43]) without either variant was used to define the novel haplogroup C7a2. The length polymorphisms of the C-tracts in region 303–309 were disregarded. The order of mutations on each uninterrupted branch segment is arbitrary. Recurrent mutations are underlined. The synonymous and non-synonymous coding-region variants in the mtDNA sequences are denoted by “/s” and “/ns”, respectively. Variants in the ribosomal RNA genes and tRNA genes are denoted by “/r” and “/t”, respectively.

Mentions: We sequenced the entire mtDNA genomes of five LHON patients (Le51, Le53, Le840, Le1192, and Le1407; GenBank accession numbers JF896797–JF896801) and the mtDNA control region sequences of three probands (Le682, Le878 and Le1561) with both m.11778G>A and m.593T>C (Table 1). Sequence variation (in either the complete mtDNA genome or in the control region) of the remaining six LHON patients was reported in our previous study [11]. According to mtDNA sequence variation (Table S2), patients Le682, Le878 and Le1561 belonged to haplogroup G1c. Analysis of the five complete mtDNA sequences indicated that these lineages belonged to haplogroups C7a2 (newly defined here based on the motif 16189-2232+A, Le51), M7b1′2′4 (Le53), D4g2 (Le840), and B5a1c1 (newly defined here based on the motif 593-5237-10325-10523, Le1192 and Le1407), respectively (Fig. 1). Besides m.11778G>A, m.593T>C and the haplogroup-specific variants in each sample, there were several private variants in each lineage (Table 2). Le51 harbored five private variants (m.6249G>A and m.7007C>T in the MT-CO1 gene, m.7990C>T in the MT-CO2 gene, and m.16183A>C and m.16519T>C in the control region). Among these, only variant m.6249G>A (p.A116T) causes an amino acid change. Le53 owned five private variants (m.1694T>C in the MT-RNR2 gene, the synonymous changes m.4137C>T in the MT-ND1 gene and m.11659C>T in the MT-ND4 gene, and m.16189T>C and m.16519T>C in the control region). Le840 had five private variants that were located in the MT-ND2 (m.4959G>A, p.A164T), MT-ND4 (m.11935T>C), MT-ND5 (m.12972A>G) genes, and the control region (m.16271T>C and m.16519T>C). Le1192 also had several private variants including three synonymous changes in the coding region (m.5237G>A in the MT-ND2 gene, m.10325G>A in the MT-ND3 gene, m.10523A>G in MT-ND4L gene) and six variants in the control region (m.64C>T, m.523-524d, m.16183A>C, m.16189T>C, m.16262C>T and m.16519T>C). There was no novel mtDNA variant [23] in these lineages. None of the three private non-synonymous variants and one mt-tRNA variant that were identified in the above patients was conserved, and all of them were reported in general populations, suggesting that these variants were most likely polymorphisms (Table 2). Similarly, the thymine at the 17th position (i.e., m.593T) of the MT-TF gene, which is located in the dihydrouracil loop (D loop) of tRNAPhe, was not conserved in eight vertebrate species (Fig. 2).


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)

Classification tree of 12 complete mtDNA sequences, plus the revised Cambridge reference sequence (rCRS) [20].Six Chinese LHON mtDNAs (including Le953 [FJ198218] [11]) had both m.593T>C and m.11778G>A. Five reported mtDNAs (GQ301863 [24], AF347007 [25], AY255137 [26], EF153821 [27], and AP008571 [28]) harbored m.593T>C. One mtDNA (EF429138 [43]) without either variant was used to define the novel haplogroup C7a2. The length polymorphisms of the C-tracts in region 303–309 were disregarded. The order of mutations on each uninterrupted branch segment is arbitrary. Recurrent mutations are underlined. The synonymous and non-synonymous coding-region variants in the mtDNA sequences are denoted by “/s” and “/ns”, respectively. Variants in the ribosomal RNA genes and tRNA genes are denoted by “/r” and “/t”, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198432&req=5

pone-0026511-g001: Classification tree of 12 complete mtDNA sequences, plus the revised Cambridge reference sequence (rCRS) [20].Six Chinese LHON mtDNAs (including Le953 [FJ198218] [11]) had both m.593T>C and m.11778G>A. Five reported mtDNAs (GQ301863 [24], AF347007 [25], AY255137 [26], EF153821 [27], and AP008571 [28]) harbored m.593T>C. One mtDNA (EF429138 [43]) without either variant was used to define the novel haplogroup C7a2. The length polymorphisms of the C-tracts in region 303–309 were disregarded. The order of mutations on each uninterrupted branch segment is arbitrary. Recurrent mutations are underlined. The synonymous and non-synonymous coding-region variants in the mtDNA sequences are denoted by “/s” and “/ns”, respectively. Variants in the ribosomal RNA genes and tRNA genes are denoted by “/r” and “/t”, respectively.
Mentions: We sequenced the entire mtDNA genomes of five LHON patients (Le51, Le53, Le840, Le1192, and Le1407; GenBank accession numbers JF896797–JF896801) and the mtDNA control region sequences of three probands (Le682, Le878 and Le1561) with both m.11778G>A and m.593T>C (Table 1). Sequence variation (in either the complete mtDNA genome or in the control region) of the remaining six LHON patients was reported in our previous study [11]. According to mtDNA sequence variation (Table S2), patients Le682, Le878 and Le1561 belonged to haplogroup G1c. Analysis of the five complete mtDNA sequences indicated that these lineages belonged to haplogroups C7a2 (newly defined here based on the motif 16189-2232+A, Le51), M7b1′2′4 (Le53), D4g2 (Le840), and B5a1c1 (newly defined here based on the motif 593-5237-10325-10523, Le1192 and Le1407), respectively (Fig. 1). Besides m.11778G>A, m.593T>C and the haplogroup-specific variants in each sample, there were several private variants in each lineage (Table 2). Le51 harbored five private variants (m.6249G>A and m.7007C>T in the MT-CO1 gene, m.7990C>T in the MT-CO2 gene, and m.16183A>C and m.16519T>C in the control region). Among these, only variant m.6249G>A (p.A116T) causes an amino acid change. Le53 owned five private variants (m.1694T>C in the MT-RNR2 gene, the synonymous changes m.4137C>T in the MT-ND1 gene and m.11659C>T in the MT-ND4 gene, and m.16189T>C and m.16519T>C in the control region). Le840 had five private variants that were located in the MT-ND2 (m.4959G>A, p.A164T), MT-ND4 (m.11935T>C), MT-ND5 (m.12972A>G) genes, and the control region (m.16271T>C and m.16519T>C). Le1192 also had several private variants including three synonymous changes in the coding region (m.5237G>A in the MT-ND2 gene, m.10325G>A in the MT-ND3 gene, m.10523A>G in MT-ND4L gene) and six variants in the control region (m.64C>T, m.523-524d, m.16183A>C, m.16189T>C, m.16262C>T and m.16519T>C). There was no novel mtDNA variant [23] in these lineages. None of the three private non-synonymous variants and one mt-tRNA variant that were identified in the above patients was conserved, and all of them were reported in general populations, suggesting that these variants were most likely polymorphisms (Table 2). Similarly, the thymine at the 17th position (i.e., m.593T) of the MT-TF gene, which is located in the dihydrouracil loop (D loop) of tRNAPhe, was not conserved in eight vertebrate species (Fig. 2).

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