在异嗜性脑白质营养不良(MLD)患者中观察到芳基硫酸酯酶A(ARSA)基因缺乏,一种溶酶体贮积病。MLD是一种严重的神经退行性疾病,以常染色体隐性遗传模式为特征。这项研究旨在将最有害的突变定位在ARSA的金属结合位点和突变位置附近的氨基酸。我们利用了一系列计算工具,包括PredictSNP,MAPP,博士-SNP,PolyPhen-1,PolyPhen-2,SIFT,SNAP,和ConSurf,为了确定从UniProt收集的MLD中可能涉及的最有害的突变,ClinVar,和HGMD。两个突变,D29N和D30H,根据致病性评估是极其有害的,养护,生物物理特征,和稳定性分析。D29和D30位于ARSA的金属相互作用区,并被发现经历翻译后修饰,特别是磷酸化。从今以后,使用磷酸化前后的分子动力学模拟(MDS)检查了金属结合对突变的深入影响。与天然相比,MDS结果显示D29N和D30H突变的偏差很大,显著的残差波动和紧密度降低证实了这一点。这些结构改变表明,这种突变可能会影响蛋白质的功能,提供个性化治疗的潜在途径,并为严重MLD患者的潜在突变特异性治疗提供基础。
The arylsulfatase A (ARSA) gene is observed to be deficient in patients with metachromatic leukodystrophy (MLD), a type of lysosomal storage disease. MLD is a severe neurodegenerative disorder characterized by an autosomal recessive inheritance pattern. This study aimed to map the most deleterious mutations at the metal binding sites of ARSA and the amino acids in proximity to the mutated positions. We utilized an array of computational tools, including PredictSNP, MAPP, PhD-SNP, PolyPhen-1, PolyPhen-2, SIFT, SNAP, and ConSurf, to identify the most detrimental mutations potentially implicated in MLD collected from UniProt, ClinVar, and HGMD. Two mutations, D29N and D30H, as being extremely deleterious based on assessments of pathogenicity, conservation, biophysical characteristics, and stability analysis. The D29 and D30 are located at the metal-interacting regions of ARSA and found to undergo post-translational modification, specifically phosphorylation. Henceforth, the in-depth effect of metal binding upon mutation was examined using molecular dynamics simulations (MDS) before and after phosphorylation. The MDS results exhibited high deviation for the D29N and D30H mutations in comparison to the native, and the same was confirmed by significant residue fluctuation and reduced compactness. These structural alterations suggest that such mutations may influence protein functionality, offering potential avenues for personalized therapeutic and providing a basis for potential mutation-specific treatments for severe MLD patients.