Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.
Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.
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DOI：
10.1371/journal.pgen.1006620
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发表时间：
2017-03
期刊：
影响因子：
4.5
通讯作者：
Maxwell PH
中科院分区：
文献类型：
--
作者：
Connor TM;Hoer S;Mallett A;Gale DP;Gomez-Duran A;Posse V;Antrobus R;Moreno P;Sciacovelli M;Frezza C;Duff J;Sheerin NS;Sayer JA;Ashcroft M;Wiesener MS;Hudson G;Gustafsson CM;Chinnery PF;Maxwell PH
肾小管间质性肾病是导致进行性肾功能衰竭的重要原因，其病因尚不完全清楚。我们分析了一个母系遗传性肾小管间质性肾病的大家系，并确定了线粒体基因组控制区的同质取代（m.547A>T）。虽然mtDNA编码序列的突变是影响多个器官的疾病的公认原因，但控制区的突变从未被证明会引起疾病。引人注目的是，我们的患者没有线粒体疾病的典型特征。患者成纤维细胞显示线粒体tRNAPhe、tRNALeu1水平降低，线粒体蛋白翻译和呼吸减少。线粒体转移证明了缺陷的线粒体传递，并且体外测定显示重链启动子的活性降低。我们还进一步鉴定了具有相同表型的在线粒体tRNAPhe中携带同质突变（m.616T>C）的激酶。因此，线粒体DNA的突变可能导致母系遗传性肾病，可能通过线粒体tRNAPhe功能降低介导。线粒体通过呼吸提供细胞的能量，利用葡萄糖和氧气产生ATP。这一过程的关键成分是由母系遗传的线粒体DNA编码的。线粒体DNA的突变通常会影响密集使用能量的器官，特别是大脑，眼睛和肌肉。在这里，我们发现了一个大家庭的线粒体DNA的启动子区的变异与肾脏疾病和其他器官的正常功能。我们发现，患者来源的线粒体不能正常产生能量，启动子活性降低，导致线粒体基因表达丧失。我们还确定了类似的突变，可能为其他原因不明的遗传性肾病病例提供了一种机制：两个细胞呼吸减少的家族携带影响线粒体苯丙氨酸tRNA的突变，这通常是线粒体蛋白翻译所需的。总之，这项研究提供了线粒体启动子中致病突变的第一个例子，并且还确定了肾脏对线粒体DNA中的不同突变特别敏感。由于这些可能是由线粒体DNA启动子区或tRNA本身的突变引起的，并且两者都减少了线粒体苯丙氨酸tRNA的量，这可能为肾脏遗传性肾病提供了潜在的统一机制。
Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNAPhe, tRNALeu1 and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNAPhe (m.616T>C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNAPhe. Mitochondria provide the cell’s energy through respiration, using glucose and oxygen to produce ATP. Critical components for this process are encoded by maternally inherited mitochondrial DNA. Mutations in mitochondrial DNA usually affect organs that use energy intensively, notably the brain, eyes and muscles. Here we have discovered a variant in the promoter region of mitochondrial DNA in a large family with kidney disease and normal function in other organs. We show that patient-derived mitochondria do not generate energy normally and have reduced promoter activity, leading to loss of mitochondrial gene expression. We also identify similar mutations that might provide a mechanism for other cases of unexplained inherited kidney disease: two families with reduced cellular respiration carry mutations affecting mitochondrial phenylalanine tRNA, normally required for mitochondrial protein translation. Together, this study provides the first example of a disease-causing mutation in the mitochondrial promoter, and also establishes that the kidney is particularly sensitive to different mutations in mitochondrial DNA. As these can arise from a mutation in the promoter region of mitochondrial DNA or in the tRNA itself, and both reduce the amount of mitochondrial phenylalanine tRNA, this may provide a potential unifying mechanism for mitochondrially inherited kidney disease.
影响因子：
4.4
作者：
Levine AP;Connor TM;Oygar DD;Neild GH;Segal AW;Maxwell PH;Gale DP
通讯作者：
Gale DP