亨廷顿病(HD)是一种慢性疾病,以舞蹈病为标志的遗传性神经退行性疾病,痴呆症,和个性的变化。HD的主要原因是突变,其特征在于位于染色体4的亨廷顿基因内的三联体重复序列(CAG)的扩增。尽管在阐明HD的分子和细胞机制方面取得了实质性进展,目前尚无有效的治疗方法。近年来,研究人员一直对研究脑脊液(CSF)作为一种生物标志物的来源感兴趣,这些生物标志物可以帮助这种疾病的诊断和治疗发展.免疫球蛋白重常数γ1(IGHG1)是在HD中发现显着增加的CSF蛋白之一。考虑到这一点,研究IGHG1有害突变可能参与该疾病的发病机制是合理的.在这项研究中,我们探讨了有害突变对IGHG1的潜在影响及其随后与HD的关联.我们评估了126个单点氨基酸取代对IGHG1蛋白的结构和功能的影响,同时利用多种计算资源,如SIFT,PolyPhen-2,FATHMM,SNPs&GomCSM,DynaMut2,MAESTROweb,PremPS,MutPred2和博士SNP。基于序列和结构的工具强调了有害和不稳定的10个氨基酸取代。随后,在这10个突变中,八种变体(Y32C,Y32D,P34S,V39E,C83R,C83Y,V85M,和H87Q)被疾病表型预测因子鉴定为致病性。最后,发现两种致病变体(Y32C和P34S)会降低蛋白质的溶解度,表明它们倾向于形成蛋白质聚集体。这些变体还在蛋白质结构内表现出更高的残余挫折。考虑到这些发现,该研究假设已鉴定的IGHG1变异体可能损害其功能,并可能导致HD发病.
Huntington\'s disease (HD) is a chronic, inherited neurodegenerative condition marked by chorea, dementia, and changes in personality. The primary cause of HD is a mutation characterized by the expansion of a triplet repeat (CAG) within the huntingtin gene located on chromosome 4. Despite substantial progress in elucidating the molecular and cellular mechanisms of HD, an effective treatment for this disorder is not available so far. In recent years, researchers have been interested in studying cerebrospinal fluid (CSF) as a source of biomarkers that could aid in the diagnosis and therapeutic development of this disorder. Immunoglobulin heavy constant gamma 1 (IGHG1) is one of the CSF proteins found to increase significantly in HD. Considering this, it is reasonable to study the potential involvement of deleterious mutations in IGHG1 in the pathogenesis of this disorder. In this study, we explored the potential impact of deleterious mutations on IGHG1 and their subsequent association with HD. We evaluated 126 single-point amino acid substitutions for their impact on the structure and functionality of the IGHG1 protein while exploiting multiple computational resources such as SIFT, PolyPhen-2, FATHMM, SNPs&Go mCSM, DynaMut2, MAESTROweb, PremPS, MutPred2, and PhD-SNP. The sequence- and structure-based tools highlighted 10 amino acid substitutions that were deleterious and destabilizing. Subsequently, out of these 10 mutations, eight variants (Y32C, Y32D, P34S, V39E, C83R, C83Y, V85M, and H87Q) were identified as pathogenic by disease phenotype predictors. Finally, two pathogenic variants (Y32C and P34S) were found to reduce the solubility of the protein, suggesting their propensity to form protein aggregates. These variants also exhibited higher residual frustration within the protein structure. Considering these findings, the study hypothesized that the identified variants of IGHG1 may compromise its function and potentially contribute to HD pathogenesis.