Nawar Noshin, Paul Anik, Mahmood Hamida Nooreen, Faisal Md Ismail, Hosen Md Ismail, Shekhar Hossain Uddin
Clinical Biochemistry and Translational Medicine Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh.
Bioinformation. 2021 Mar 31;17(3):424-438. doi: 10.6026/97320630017424. eCollection 2021.
Partner and Localizer of BRCA2 or PALB2 is a typical tumor suppressor protein, that responds to DNA double stranded breaks through homologous recombination repair. Heterozygous mutations in PALB2 are known to contribute to the susceptibility of breast and ovarian cancer. However, there is no comprehensive study characterizing the structural and functional impacts of SNPs located in the PALB2 gene. Therefore, it is of interest to document a comprehensive analysis of coding and non-coding SNPs located at the PALB2 loci using in silico tools. The data for 1455 non-synonymous SNPs (nsSNPs) located in the PALB2 loci were retrieved from the dbSNP database. Comprehensive characterization of the SNPs using a combination of in silico tools such as SIFT, PROVEAN, PolyPhen, PANTHER, PhD-SNP, Pmut, MutPred 2.0 and SNAP-2, identified 28 functionally important SNPs. Among these, 16 nsSNPs were further selected for structural analysis using conservation profile and protein stability. The most deleterious nsSNPs were documented within the WD40 domain of PALB2. A general outline of the structural consequences of each variant was developed using the HOPE project data. These 16 mutant structures were further modelled using SWISS Model and three most damaging mutant models (rs78179744, rs180177123 and rs45525135) were identified. The non-coding SNPs in the 3' UTR region of the PALB2 gene were analyzed for altered miRNA target sites. The comprehensive characterization of the coding and non-coding SNPs in the PALB2 locus has provided a list of damaging SNPs with potential disease association. Further validation through genetic association study will reveal their clinical significance.
BRCA2的伴侣和定位蛋白（PALB2）是一种典型的肿瘤抑制蛋白，它通过同源重组修复对DNA双链断裂作出反应。已知PALB2中的杂合突变会导致乳腺癌和卵巢癌易感性增加。然而，目前尚无全面研究来表征位于PALB2基因中的单核苷酸多态性（SNP）对结构和功能的影响。因此，利用计算机工具对位于PALB2基因座的编码和非编码SNP进行全面分析很有意义。从dbSNP数据库中检索了位于PALB2基因座的1455个非同义SNP（nsSNP）的数据。使用诸如SIFT、PROVEAN、PolyPhen、PANTHER、PhD-SNP、Pmut、MutPred 2.0和SNAP-2等计算机工具对这些SNP进行综合表征，确定了28个功能重要的SNP。其中，进一步选择了16个nsSNP进行保守性分析和蛋白质稳定性的结构分析。在PALB2的WD40结构域中记录了最有害的nsSNP。利用HOPE项目数据绘制了每个变体结构后果的总体概述。使用SWISS模型对这16个突变结构进行进一步建模，并确定了三个最具破坏性的突变模型（rs78179744、rs180177123和rs45525135）。分析了PALB2基因3'UTR区域中的非编码SNP是否存在改变的miRNA靶位点。对PALB2基因座中编码和非编码SNP的综合表征提供了一系列具有潜在疾病关联的有害SNP。通过遗传关联研究进行进一步验证将揭示它们的临床意义。
