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Functional analysis of a novel POLγA mutation associated with a severe perinatal mitochondrial encephalomyopathy
Neuromuscular Disorders ( IF 2.7 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.nmd.2021.01.004
Niklas Darin 1 , Triinu Siibak 2 , Bradley Peter 2 , Carola Hedberg-Oldfors 3 , Gittan Kollberg 3 , Vassili Kalbin 2 , Ali-Reza Moslemi 3 , Bertil Macao 2 , Anders Oldfors 3 , Maria Falkenberg 2
Affiliation  

Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POLA) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POLA often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POLA mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death. Muscle biopsy identified scattered COX-deficient muscle fibers, respiratory chain dysfunction and mtDNA depletion. We identified a novel POLA mutation (p.His1134Tyr) in trans with the previously identified p.Thr251Ile/Pro587Leu double mutant. Biochemical characterization of the purified recombinant POLγA variants showed that the p.His1134Tyr mutation caused severe polymerase dysfunction. The p.Thr251Ile/Pro587Leu mutation caused reduced polymerase function in conditions of low dNTP concentration that mimic postmitotic tissues. Critically, when p.His1134Tyr and p.Thr251Ile/Pro587Leu were combined under these conditions, mtDNA replication was severely diminished and featured prominent stalling. Our data provide a molecular explanation for the patient ́s mtDNA depletion and clinical features, particularly in tissues such as brain and muscle that have low dNTP concentration.

中文翻译:

与严重围产期线粒体脑肌病相关的新型 POLγA 突变的功能分析

线粒体 DNA 聚合酶 γ 催化亚基 (POLA) 中的突变会导致线粒体 DNA (mtDNA) 的突变、缺失和耗竭,从而损害线粒体 DNA (mtDNA) 的稳定性。POLA 突变的患者通常在疾病严重程度和发病年龄方面存在显着差异。在这项工作中,我们研究了 POLA 突变在一名患有罕见且非常严重的疾病表型的患者中的功能后果,其特征是产前发病并伴有宫内生长受限、出生乳酸性酸中毒、脑病、肝病、肌病和早逝。肌肉活检发现散在的 COX 缺陷肌纤维、呼吸链功能障碍和 mtDNA 耗竭。我们与先前鉴定的 p.Thr251Ile/Pro587Leu 双突变体反式鉴定了一种新的 POLA 突变(p.His1134Tyr)。纯化的重组 POLγA 变体的生化特征表明 p.His1134Tyr 突变导致严重的聚合酶功能障碍。在模拟有丝分裂后组织的低 dNTP 浓度条件下,p.Thr251Ile/Pro587Leu 突变导致聚合酶功能降低。至关重要的是,当 p.His1134Tyr 和 p.Thr251Ile/Pro587Leu 在这些条件下结合时,mtDNA 复制会严重减少,并具有明显的停滞。我们的数据为患者的 mtDNA 耗竭和临床特征提供了分子解释,尤其是在大脑和肌肉等 dNTP 浓度较低的组织中。在模拟有丝分裂后组织的低 dNTP 浓度条件下,Thr251Ile/Pro587Leu 突变导致聚合酶功能降低。至关重要的是,当 p.His1134Tyr 和 p.Thr251Ile/Pro587Leu 在这些条件下结合时,mtDNA 复制会严重减少,并具有明显的停滞。我们的数据为患者的 mtDNA 耗竭和临床特征提供了分子解释,尤其是在大脑和肌肉等 dNTP 浓度较低的组织中。在模拟有丝分裂后组织的低 dNTP 浓度条件下,Thr251Ile/Pro587Leu 突变导致聚合酶功能降低。至关重要的是,当 p.His1134Tyr 和 p.Thr251Ile/Pro587Leu 在这些条件下结合时,mtDNA 复制会严重减少,并具有明显的停滞。我们的数据为患者的 mtDNA 耗竭和临床特征提供了分子解释,尤其是在大脑和肌肉等 dNTP 浓度较低的组织中。
更新日期:2021-01-01
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