Mehboob Muhammad Zubair, Hamid Arslan, Senthil Kumar Jeevotham, Lei Xia
Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK, 74078, USA.
Institute for Molecular Biomedicine, Department of Molecular Immunology and Cell Biology, University of Bonn, 53115, Bonn, Germany.
BMC Cancer. 2025 Feb 20;25(1):304. doi: 10.1186/s12885-025-13685-0.
Previous genome-wide association studies have linked three missense single nucleotide polymorphisms (SNPs) in C1q/TNF-related protein 6 (CTRP6) to diseases such as type 1 diabetes and autoimmune diseases. However, the potential association of newly identified missense CTRP6 variants with diseases, especially cancer, remains unclear.
We used several pathogenicity prediction algorithms to identify deleterious mutations within the highly conserved C1q domain of human CTRP6, following the retrieval of all SNPs from the Ensembl database. We systematically analyzed the effects of these mutations on the protein's stability, flexibility, structural conformation, compactness, stiffness, and overall functionality using various bioinformatics tools. Additionally, we investigated the association of these mutations with different cancer types using the cBioPortal and canSAR databases.
We identified 11 detrimental missense SNPs within the C1q domain, a region critical for this protein's functionality. Using various computational methods, we predicted the functional impact of these missense variants and assessed their effects on the stability and flexibility of the CTRP6 structure. Molecular dynamics simulations revealed significant structural differences between the native and mutated structures, including changes in structural conformation, compactness, solvent accessibility, and flexibility. Additionally, our study shows a strong association between two mutations, G181S and R247W, and certain types of cancer: colon adenocarcinoma and uterine corpus endometrial carcinoma, respectively. We also found that the mutational status of CTRP6 and other cancer-related genes, such as MAP2K3, p16, TP53, and JAK1, affected each other's expression, potentially contributing to cancer development.
Our screening and predictive analysis of pathogenic missense variants in CTRP6 advance the understanding of the functional implications of these mutations, potentially facilitating more focused and efficient research in the future.
先前的全基因组关联研究已将C1q/TNF相关蛋白6（CTRP6）中的三个错义单核苷酸多态性（SNP）与1型糖尿病和自身免疫性疾病等疾病联系起来。然而，新发现的CTRP6错义变体与疾病，尤其是癌症之间的潜在关联仍不清楚。
我们从Ensembl数据库中检索了所有SNP，然后使用几种致病性预测算法来识别人类CTRP6高度保守的C1q结构域内的有害突变。我们使用各种生物信息学工具系统地分析了这些突变对蛋白质稳定性、灵活性、结构构象、紧凑性、刚度和整体功能的影响。此外，我们使用cBioPortal和canSAR数据库研究了这些突变与不同癌症类型的关联。
我们在C1q结构域中鉴定出11个有害的错义SNP，该区域对该蛋白质的功能至关重要。我们使用各种计算方法预测了这些错义变体的功能影响，并评估了它们对CTRP6结构稳定性和灵活性的影响。分子动力学模拟揭示了天然结构和突变结构之间的显著结构差异，包括结构构象、紧凑性、溶剂可及性和灵活性的变化。此外，我们的研究表明，两种突变G181S和R247W分别与某些类型的癌症：结肠腺癌和子宫内膜癌有很强的关联。我们还发现CTRP6和其他癌症相关基因（如MAP2K3、p16、TP53和JAK1）的突变状态相互影响彼此的表达，可能促进癌症的发展。
我们对CTRP6致病性错义变体的筛选和预测分析推进了对这些突变功能影响的理解，可能有助于未来更有针对性和高效的研究。
