Siibak Triinu, Clemente Paula, Bratic Ana, Bruhn Helene, Kauppila Timo E S, Macao Bertil, Schober Florian A, Lesko Nicole, Wibom Rolf, Naess Karin, Nennesmo Inger, Wedell Anna, Peter Bradley, Freyer Christoph, Falkenberg Maria, Wredenberg Anna
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg SE-405?30, Sweden.
Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden.
Hum Mol Genet. 2017 Jul 1;26(13):2515-2525. doi: 10.1093/hmg/ddx146.
Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction.
线粒体DNA聚合酶（POLG）的突变与多种临床表现相关，从阿尔珀斯综合征中早发性致命性脑病到慢性进行性外眼肌麻痹。大多数突变与线粒体DNA（mtDNA）完整性和维持的紊乱有关。在分子水平上，根据突变在酶中的位置，要么导致mtDNA耗竭，要么导致多个mtDNA缺失的积累，在某些情况下，这些分子变化与临床表现相关。我们鉴定出一名携带POLG中显性p.Y955H突变的患者，表现为严重的早发性多系统线粒体疾病，伴有双侧感音神经性听力损失、白内障、肌病和肝功能衰竭。我们结合黑腹果蝇疾病模型和体外生物化学分析，将p.Y955H突变与已充分记录的p.Y955C突变的分子后果进行比较。我们证明这两种突变都影响mtDNA复制并表现出显性负效应，其中p.Y955H等位基因导致更严重的聚合酶功能障碍。
