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Mutant POLG2 Disrupts DNA Polymerase γ Subunits and Causes Progressive External Ophthalmoplegia

机译:突变体POLG2破坏DNA聚合酶γ亚基并导致进行性眼外肌麻痹

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摘要

DNA polymerase γ (pol γ) is required to maintain the genetic integrity of the 16,569-bp human mitochondrial genome (mtDNA). Mutation of the nuclear gene for the catalytic subunit of pol γ (POLG) has been linked to a wide range of mitochondrial diseases involving mutation, deletion, and depletion of mtDNA. We describe a heterozygous dominant mutation (c.1352G→A/p.G451E) in POLG2, the gene encoding the p55 accessory subunit of pol γ, that causes progressive external ophthalmoplegia with multiple mtDNA deletions and cytochrome c oxidase (COX)–deficient muscle fibers. Biochemical characterization of purified, recombinant G451E-substituted p55 protein in vitro revealed incomplete stimulation of the catalytic subunit due to compromised subunit interaction. Although G451E p55 retains a wild-type ability to bind DNA, it fails to enhance the DNA-binding strength of the p140-p55 complex. In vivo, the disease most likely arises through haplotype insufficiency or heterodimerization of the mutated and wild-type proteins, which promote mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype.
机译:需要DNA聚合酶γ(polγ)来维持16569 bp的人类线粒体基因组(mtDNA)的遗传完整性。 polγ(POLG)催化亚基的核基因突变已与广泛的线粒体疾病相关,涉及mtDNA的突变,缺失和耗竭。我们描述了POLG2中的杂合优势突变(c.1352G→A / p.G451E),该基因编码polγ的p55辅助亚基,可导致进行性眼外肌麻痹,并伴有多个mtDNA缺失和细胞色素C氧化酶(COX)缺陷型肌肉纤维。体外纯化的重组G451E取代的p55蛋白的生化特征表明,由于受损的亚基相互作用,催化亚基的刺激不完全。尽管G451E p55保留了结合DNA的野生型能力,但无法增强p140-p55复合物的DNA结合强度。在体内,该疾病最有可能是由于突变型和野生型蛋白的单倍型不足或异源二聚化而引起的,这些蛋白通过使DNA复制叉停滞而促进mtDNA缺失。 mtDNA缺失的逐步积累导致肌肉纤维中COX缺乏并导致临床表型。

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