A MITOCHONDRIAL-DNA CLONE IS ASSOCIATED WITH INCREASED RISK FOR ALZHEIMER-DISEASE
A MITOCHONDRIAL-DNA CLONE IS ASSOCIATED WITH INCREASED RISK FOR ALZHEIMER-DISEASE
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DOI：
10.1073/pnas.92.15.6892
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发表时间：
1995-07-18
影响因子：
11.1
通讯作者：
CORTOPASSI, G
中科院分区：
文献类型：
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作者：
HUTCHIN, T;CORTOPASSI, G
严重的线粒体基因突变导致特定人体组织的早期退化;轻度线粒体突变可能导致生命后期的退化。据报道，在4336位的突变在患有阿尔茨海默病（AD）和帕金森病的个体中以增加的频率发生[Shoffner，J.M.，布朗，M。D、Torroni，A，Lott，M. T.，卡贝尔，M. F.、米拉，S。美国，比尔，M. F.、杨角C.的方法，吉尔林，M.，Salvo，R，Watts，R L.，容科斯，J.L.，汉森湖一、克莱恩，B。J.，Fayad，M.，雷科德角L.和Wallace，D. C.（1993）Genomics 17，171-184]。我们通过对72例AD尸检和296例种族和年龄匹配对照的病例对照研究设计，研究了这种突变导致AD过度风险的概念。AD尸检中4336 G突变的发生频率高于年龄匹配的对照组，差异具有统计学意义。携带4336 G突变的mtDNA的进化分析表明，它们之间的关系比其他mtDNA更密切，这与该突变的单一起源模型一致。与导致早发性疾病的线粒体基因组的远缘相关性和异质性形成鲜明对比的是，线粒体DNA的紧密进化相关性和同质性增加了晚发性疾病的风险。这种二分法可以解释为，在人类进化的大部分过程中，缺乏针对突变的选择，这些突变在老年时赋予了一种表型。我们估计，美国约有150万白人携带4336 G突变，在其一生中发生线粒体AD的风险显著增加。提出了4336 G介导的细胞死亡的机制。
Severe mitochondrial genetic mutations lead to early degeneration of specific human tissues; milder mitochondrial mutations may cause degeneration at a later point in life. A mutation at position 4336 was reported to occur at increased frequency in individuals with Alzheimer disease (AD) and Parkinson disease [Shoffner, J. M., Brown, M. D., Torroni, A, Lott, M. T., Cabell, M. F., Mirra, S. S., Beal, M. F., Yang, C.-C., Gearing, M., Salvo, R, Watts, R. L., Juncos, J. L., Hansen, L. A., Crain, B. J., Fayad, M., Reckord, C. L. and Wallace, D. C. (1993) Genomics 17, 171-184]. We have investigated the notion that this mutation leads to excess risk of AD by using a case-control study design of 72 AD autopsies and 296 race- and age-matched controls. The 4336G mutation occurred at higher frequency in AD autopsies than age-matched controls, a statistically significant difference. Evolutionary analysis of mtDNAs bearing the 4336G mutation indicated they were more closely related to each other than to other mtDNAs, consistent with the model of a single origin for this mutation. The tight evolutionary relatedness and homoplasmy of mtDNAs that confer elevated risk for a late-onset disease contrast strikingly with the distant relatedness and heteroplasmy of mitochondrial genomes that cause early onset disease. The dichotomy can be explained by a lack of selection against mutations that confer a phenotppe at advanced age during most of the evolution of humans. We estimate that approximate to 1.5 million Caucasians in the United States bear the 4336G mutation and are at significantly increased risk of developing mitochondrial AD in their lifetime. A mechanism for 4336G-mediated cell death is proposed.