title: Is mitochondrial tRNA(phe) variant m.593T>C a synergistically pathogenic mutation in Chinese LHON families with m.11778G>A?
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.
authors: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors: A-Mei
authors: AM
authors: Zhang
authors: Hans-Jürgen
authors: HJ
authors: Bandelt
authors: Xiaoyun
authors: X
authors: Jia
authors: Wen
authors: W
authors: Zhang
authors: Shiqiang
authors: S
authors: Li
authors: Dandan
authors: D
authors: Yu
authors: Dong
authors: D
authors: Wang
authors: Xin-Ying
authors: XY
authors: Zhuang
authors: Qingjiong
authors: Q
authors: Zhang
authors: Yong-Gang
authors: YG
authors: Yao
mesh_terms: D000818:Animals; D001483:Base Sequence; D002681:China; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009690:Nucleic Acid Conformation; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D017433:Protein Structure, Secondary; D012360:RNA, Transfer, Phe / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial; D012360:RNA, Transfer, Phe