Exploring Single Nucleotide Polymorphisms in ITGAV for Gastric, Pancreatic and Liver Malignancies: An Approach towards Biomarker Discovery

2020 ◽  
Vol 23 ◽  
Author(s):  
Shreya Bhattacharya ◽  
Pragati Prasad Sah ◽  
Arundhati Banerjee ◽  
Sujay Ray
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Biomarker Discovery ◽  
Solvent Accessibility ◽  
Structure Stability ◽  
Nucleotide Polymorphisms ◽  
Liver Malignancies ◽  
Single Nucleotide ◽  
Integrin Αv

Background: Integrin αV, encoded by ITGAV gene is one of the most studied protein subunits, closely associated with liver, pancreatic and stomach cancer progression and metastasis via regulation of angiogenesis. Occurrence of Single Nucleotide Polymorphisms (SNPs) in cancer-associated proteins is a key determinant for varied susceptibility of an individual towards cancer. Methodology: The study investigated the deleterious effects of these cancer-associated SNPs on the protein’s structure, stability and cancer causing potential using an in silico approach. Numerous computational tools were employed that identified the most deleterious cancer-associated SNPs and those to get actively involved in post-translational modifications. Impact of these SNPs on the protein structure, function and stability was also examined. Conclusion and Future Scope: A total 63 non-synonymous SNPs in ITGAV gene were observed to be associated in these three gastrointestinal cancers and among this 63, 19 were the most deleterious ones. The structural and functional importance of residues altered by most damaging SNPs was analyzed through evolutionary conservation and solvent accessibility. The study also elucidated three-dimensional structures of the 19 most damaging mutants. The analysis of conformational variation identified 5SNPs (D379Y, G188E, G513V, L950P, and R540L) in integrin αV, which influence protein’s structure. Three calcium binding sites were predicted at residues: D379, G384 and G408 and a peptide binding site at residue: R369 in integrin αV. Therefore, SNPs D379Y, G384C, G408R and R369W have the potential to alter the binding properties of the protein. Screening and characterization of deleterious SNPs could advance novel biomarker discovery and therapeutic development in future.

scholarly journals Functional and structural analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the MYB oncoproteins associated with human cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shu Wen Lim ◽  
Kennet JunKai Tan ◽  
Osman Mohd Azuraidi ◽  
Maran Sathiya ◽  
Ee Chen Lim ◽  
...  
Keyword(s):  
Dna Binding ◽  
Single Nucleotide Polymorphisms ◽  
Cancer Progression ◽  
Posttranslational Modifications ◽  
Protein Function ◽  
Biomarker Discovery ◽  
Human Cancer ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Cancer Management

AbstractMYB proteins are highly conserved DNA-binding domains (DBD) and mutations in MYB oncoproteins have been reported to cause aberrant and augmented cancer progression. Identification of MYB molecular biomarkers predictive of cancer progression can be used for improving cancer management. To address this, a biomarker discovery pipeline was employed in investigating deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in predicting damaging and potential alterations on the properties of proteins. The nsSNP of the MYB family; MYB, MYBL1, and MYBL2 was extracted from the NCBI database. Five in silico tools (PROVEAN, SIFT, PolyPhen-2, SNPs&GO and PhD-SNP) were utilized to investigate the outcomes of nsSNPs. A total of 45 nsSNPs were predicted as high-risk and damaging, and were subjected to PMut and I-Mutant 2.0 for protein stability analysis. This resulted in 32 nsSNPs with decreased stability with a DDG score lower than − 0.5, indicating damaging effect. G111S, N183S, G122S, and S178C located within the helix-turn-helix (HTH) domain were predicted to be conserved, further posttranslational modifications and 3-D protein analysis indicated these nsSNPs to shift DNA-binding specificity of the protein thus altering the protein function. Findings from this study would help in the field of pharmacogenomic and cancer therapy towards better intervention and management of cancer.

scholarly journals Prediction and Structural Comparison of Deleterious Coding Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in Human LEP Gene Associated with Obesity

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Hind Bouafi ◽  
Sara Bencheikh ◽  
AL Mehdi Krami ◽  
Imane Morjane ◽  
Hicham Charoute ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Public Health Problem ◽  
Computational Prediction ◽  
The Body ◽  
Structure Stability ◽  
Major Public Health Problem ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Lep Gene ◽  
The Impact

Leptin is a peptide hormone that regulates fat stores in the body and appetite by controlling the feeling of satiety. This hormone is secreted by the white adipose tissue and plays a role in the storage and mobilization of fatty acids. Mutations of the LEP gene have been associated with obesity in different populations; it is a multifactorial disease that constitutes a major public health problem. In this study, we evaluated the impact of missense SNPs in the LEP gene extracted from dbSNP using 8 computational prediction tools. Out of the total of 4337 SNPs, 93 were nsSNPs (nonsynonymous single nucleotide polymorphisms). Among 93 nsSNPs, 12 (S46L, G59S, D61N, D100N, N103K, C117S, D76V, S88C, P90R, I95N, L161R, and R105W) variants were predicted to be the most deleterious by prediction software. On these 12 deleterious SNPs, 8 variants (S46L, G59S, D61N, D100N, N103K, C117S, L161R, and R105W) were located in the conserved positions and showed a decrease in structure stability which was evaluated by I-Mutant and Mupro. Then, by analyzing the different interactions between different amino acids in wild and mutated proteins, we assessed the structural impact of the deleterious modifications using the YASARA software. Among 8 deleterious nsSNPs, we revealed structure changes in the 6 variants S46L, G59S, D100N, L103K, R105W, L161R, two of which R105W, N103K were previously reported as associated with obesity. Our study suggests 6 deleterious mutations could play an important role in contributing to human obesity and worth to be included in association and functional studies, then may be a drug target.

Matrix Metalloproteinase Single-Nucleotide Polymorphisms and Haplotypes Predict Breast Cancer Progression

2007 ◽  
Vol 13 (22) ◽  
pp. 6673-6680 ◽  
Author(s):  
Simon Hughes ◽  
Olorunsola Agbaje ◽  
Rebecca L. Bowen ◽  
Deborah L. Holliday ◽  
Jacqueline A. Shaw ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Nucleotide Polymorphisms ◽  
Matrix Metalloproteinase ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

scholarly journals Predicting the Most Deleterious Missense Nonsynonymous Single-Nucleotide Polymorphisms of Hennekam Syndrome-Causing CCBE1 Gene, In Silico Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Khyber Shinwari ◽  
Liu Guojun ◽  
Svetlana S. Deryabina ◽  
Mikhail A. Bolkov ◽  
Irina A. Tuzankina ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
In Silico ◽  
Calcium Binding ◽  
Phosphorylation Site ◽  
In Silico Analysis ◽  
Matrix Remodeling ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Pathogenic Variants ◽  
Hennekam Syndrome

Hennekam lymphangiectasia-lymphedema syndrome has been linked to single-nucleotide polymorphisms in the CCBE1 (collagen and calcium-binding EGF domains 1) gene. Several bioinformatics methods were used to find the most dangerous nsSNPs that could affect CCBE1 structure and function. Using state-of-the-art in silico tools, this study examined the most pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) that disrupt the CCBE1 protein and extracellular matrix remodeling and migration. Our results indicate that seven nsSNPs, rs115982879, rs149792489, rs374941368, rs121908254, rs149531418, rs121908251, and rs372499913, are deleterious in the CCBE1 gene, four (G330E, C102S, C174R, and G107D) of which are the highly deleterious, two of them (G330E and G107D) have never been seen reported in the context of Hennekam syndrome. Twelve missense SNPs, rs199902030, rs267605221, rs37517418, rs80008675, rs116596858, rs116675104, rs121908252, rs147974432, rs147681552, rs192224843, rs139059968, and rs148498685, are found to revert into stop codons. Structural homology-based methods and sequence homology-based tools revealed that 8.8% of the nsSNPs are pathogenic. SIFT, PolyPhen2, M-CAP, CADD, FATHMM-MKL, DANN, PANTHER, Mutation Taster, LRT, and SNAP2 had a significant score for identifying deleterious nsSNPs. The importance of rs374941368 and rs200149541 in the prediction of post-translation changes was highlighted because it impacts a possible phosphorylation site. Gene-gene interactions revealed CCBE1’s association with other genes, showing its role in a number of pathways and coexpressions. The top 16 deleterious nsSNPs found in this research should be investigated further in the future while researching diseases caused CCBE1 gene specifically HS. The FT web server predicted amino acid residues involved in the ligand-binding site of the CCBE1 protein, and two of the substitutions (R167W and T153N) were found to be involved. These highly deleterious nsSNPs can be used as marker pathogenic variants in the mutational diagnosis of the HS syndrome, and this research also offers potential insights that will aid in the development of precision medicines. CCBE1 proteins from Hennekam syndrome patients should be tested in animal models for this purpose.

scholarly journals Computational and Mass Spectrometry-Based Approach Identify Deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in JMJD6

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4653
Author(s):  
Tianqi Gong ◽  
Lujie Yang ◽  
Fenglin Shen ◽  
Hao Chen ◽  
Ziyue Pan ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Single Nucleotide Polymorphisms ◽  
Cancer Progression ◽  
Three Dimensional ◽  
Prediction Method ◽  
Mrna Splicing ◽  
Dimensional Structure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Liquid Chromatography Tandem Mass

The jumonji domain-containing protein 6 (JMJD6) gene catalyzes the arginine demethylation and lysine hydroxylation of histone and a growing list of its known substrate molecules, including p53 and U2AF65, suggesting a possible role in mRNA splicing and transcription in cancer progression. Mass spectrometry-based technology offers the opportunity to detect SNP variants accurately and effectively. In our study, we conducted a combined computational and filtration workflow to predict the nonsynonymous single nucleotide polymorphisms (nsSNPs) present in JMJD6, followed by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and validation. The computational approaches SIFT, PolyPhen-2, SNAP, I-Mutant 2.0, PhD-SNP, PANTHER, and SNPS&GO were integrated to screen out the predicted damaging/deleterious nsSNPs. Through the three-dimensional structure of JMJD6, H187R (rs1159480887) was selected as a candidate for validation. The validation experiments showed that the mutation of this nsSNP in JMJD6 obviously affected mRNA splicing or the transcription of downstream genes through the reduced lysyl-hydroxylase activity of its substrates, U2AF65 and p53, further indicating the accuracy of this prediction method. This research provides an effective computational workflow for researchers with an opportunity to select prominent deleterious nsSNPs and, thus, remains promising for examining the dysfunction of proteins.

Development of a simple method for the determination of single nucleotide polymorphisms

2010 ◽  
Vol 34 (8) ◽  
pp. S75-S75
Author(s):  
Weifeng Zhu ◽  
Zhuoqi Liu ◽  
Daya Luo ◽  
Xinyao Wu ◽  
Fusheng Wan
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Simple Method ◽  
Single Nucleotide

Sex Differences in Childhood Associations between DNA Markers and General Cognitive Ability

2007 ◽  
Vol 28 (3) ◽  
pp. 161-164 ◽  
Author(s):  
Rosalind Arden ◽  
Nicole Harlaar ◽  
Robert Plomin
Keyword(s):  
Sex Differences ◽  
Single Nucleotide Polymorphisms ◽  
Cognitive Ability ◽  
Dna Markers ◽  
Community Sample ◽  
Nucleotide Polymorphisms ◽  
General Cognitive Ability ◽  
Single Nucleotide ◽  
The Difference

Abstract. An association between intelligence at age 7 and a set of five single-nucleotide polymorphisms (SNPs) has been identified and replicated. We used this composite SNP set to investigate whether the associations differ between boys and girls for general cognitive ability at ages 2, 3, 4, 7, 9, and 10 years. In a longitudinal community sample of British twins aged 2-10 (n > 4,000 individuals), we found that the SNP set is more strongly associated with intelligence in males than in females at ages 7, 9, and 10 and the difference is significant at 10. If this finding replicates in other studies, these results will constitute the first evidence of the same autosomal genes acting differently on intelligence in the two sexes.

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