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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans
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Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

机译：线粒体DNA变异与Leber遗传性视神经病变和高海拔藏人

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摘要

The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease.
机译：轻度致病性mtDNA突变与种群多态性之间的区别可能是模棱两可的，因为它们都是同质的，改变了保守功能，并与疾病相关。这种歧义的一种可能解释是，相同的变体在不同的上下文中可能具有不同的后果。这种情况是NADH脱氢酶亚基1（ND1）核苷酸3394T> C（Y30H）的变体。该变异与Leber遗传性视神经病变有关，在亚洲B4c和F1单倍体背景下，其复杂I活动和细胞呼吸降低了7％至28％。但是，包含共同的3394T等位基因的B4c和F1 mtDNA之间的复杂I活性也可以相差30％。在亚洲，3394C变异体最常与M9单倍群相关，在低海拔时很少见，但频率随海拔升高而增加，平均达到藏族mtDNA的25％（奇数比= 23.7）。在高海拔的藏族和印度族人群中，3394C变异出现在五个不同的大单倍体M单倍体背景上，并在西藏的M9背景和印度Deccan高原的C4a4背景上富集（优势比= 21.9）。当存在于M9背景上时，3394C变体与等于或高于B4c和F1背景上的3394T变体的I活动相关。因此，3394C变体可能有害或有益，这取决于其单倍型和环境。因此，该mtDNA变体满足了易患“复杂”疾病的常见变体的标准。

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    Fuyun Ji; Mark S. Sharpley; Olga Derbeneva; Leonardo Scherer Alves; Pin Qian; Yaoli Wang; Dimitra Chalkia; Maria Lvova; Jiancheng Xu; Wei Yao; Mariella Simon; Julia Platt; Shiqin Xu; Alessia Angelin; Antonio Davila; Taosheng Huang; Ping H. Wang; Lee-Ming Chuang; Lorna G. Moore; Guisheng Qian; Douglas C. Wallace;

  • 作者单位

    Institute of Human Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    lnstitute of Field Internal Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China;

    Institute of Human Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Institute of Human Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104;

    Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Department of Medicine, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

    Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan;

    Graduate School of Arts and Sciences, Wake Forest University, Winston-Salem, NC 27157;

    Institute of Human Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China;

    Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104,Center for Molecular and Mitochondrial Medicine and Genetics, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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  • 关键词

    adaptation; hypoxia; OXPHOS; complex disease;

    机译：适应;缺氧OXPHOS;复杂疾病;

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