PDF(Pubmed)
Abstract：
Friedreich\'s Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys®), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.
摘要：
Friedreich的共济失调（FRDA）是遗传性共济失调最普遍的形式，以渐进性运动共济失调为标志，振动灵敏度的损失，和骨骼畸形，严重影响日常运作。迄今为止,唯一可用于治疗FRDA的药物是Omaveloxolone（Skyclarys®），最近被FDA批准。人类共济失调蛋白（FXN）基因内的错义突变，负责细胞内铁稳态调节，与FRDA开发有关。这些突变诱导FXN功能障碍，促进线粒体铁积累和增强的氧化应激，最终触发神经元细胞死亡途径。本研究从文献和数据库搜索中合并了226种FXN遗传变异，以前只有18个特征。预测分析显示，FXN突变的有害和不稳定预测普遍存在，主要影响对蛋白质功能至关重要的保守残基。此外,一个准确的，构建了人体FXN的综合三维模型，作为产生遗传变异I154F和W155R的基础。这些变种,因其严重的临床意义而被选中，进行了分子动力学(MD)模拟，揭示了其N端段的灵活性和基本的动态变化，包含对蛋白质成熟至关重要的FXN42，FXN56和FXN78结构域。因此，我们的发现表明，由I154F和W155R突变诱导的FXN42，FXN56和FXN78结构域中潜在的相互作用谱紊乱，与现有文献保持一致。
