In silico screening and identification of deleterious missense SNPs along with their effects on CD-209 gene: An insight to CD-209 related-diseases

Kakar, Mohib Ullah; Matloob, Muhammad; Dai, Ruitong; Deng, Yulin; Ullah, Kifayat; Kakar, Ihsan Ullah; Khaliq, Ghulam; Umer, Muhammad; Bhutto, Zhoaib Ahmed; Fazlani, Sarfarz Ali; Mehboob, Muhammad Zubair

doi:10.1371/journal.pone.0247249

Cited by 8 publications

(7 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PROVEAN server utilizes the principal sequence of the protein and its sequence homologies, which are investigated by dint of BLAST in NCBI database. The prediction of PROVEAN is based on a scoring system where the cut-off value is −2.5 [ 54 ]. On the basis of this scoring system, amino acid substitution with PROVEAN score less than −2.5 will be determined as a deleterious mutation, while PROVEAN score greater than −2.5 will be determined as a neutral mutation [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene

Laskar,

Bappy,

Hossain

et al. 2023

International Journal of Genomics

View full text Add to dashboard Cite

Mesenchymal–epithelial transition (MET) factor is a proto-oncogene encoding tyrosine kinase receptor with hepatocyte growth factor (HGF) or scatter factor (SF). It is found on the human chromosome number 7 and regulates the diverse cellular mechanisms of the human body. The impact of mutations occurring in the MET gene is demonstrated by their detrimental effects on normal cellular functions. These mutations can change the structure and function of MET leading to different diseases such as lung cancer, neck cancer, colorectal cancer, and many other complex syndromes. Hence, the current study focused on finding deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) and their subsequent impact on the protein’s structure and functions, which may contribute to the emergence of cancers. These nsSNPs were first identified utilizing computational tools like SIFT, PROVEAN, PANTHER-PSEP, PolyPhen-2, I-Mutant 2.0, and MUpro. A total of 45359 SNPs of MET gene were accumulated from the database of dbSNP, and among them, 1306 SNPs were identified as non-synonymous or missense variants. Out of all 1306 nsSNPs, 18 were found to be the most deleterious. Moreover, these nsSNPs exhibited substantial effects on structure, binding affinity with ligand, phylogenetic conservation, secondary structure, and post-translational modification sites of MET, which were evaluated using MutPred2, RaptorX, ConSurf, PSIPRED, and MusiteDeep, respectively. Also, these deleterious nsSNPs were accompanied by changes in properties of MET like residue charge, size, and hydrophobicity. These findings along with the docking results are indicating the potency of the identified SNPs to alter the structure and function of the protein, which may lead to the development of cancers. Nonetheless, Genome-wide association study (GWAS) studies and experimental research are required to confirm the analysis of these nsSNPs.

show abstract

Section: Resultsmentioning

confidence: 99%

An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene

Laskar,

Bappy,

Hossain

et al. 2023

International Journal of Genomics

View full text Add to dashboard Cite

show abstract

“…Furthermore, the predictions of all algorithms were found to correlate significantly with each other independently, while I-mutant3.0 showed a slight negative correlation with MutationAssessor. Since each algorithm uses different parameters for SNP assessment, SNPs that retrieved more positive responses in different SNP algorithms are more likely to be deleterious [ 22 , 23 ]. Therefore, SNPs that were considered deleterious by at least ten different in silico algorithms were classified as high-risk nsSNPs in this study.…”

Section: Resultsmentioning

confidence: 99%

“…Generally, residues, which are critical for protein stability, biomolecular interactions, and functions, are more usually conserved than others [ 22 ]. Therefore, SNPs in the conserved area are likely to be more pathogenic than those present in the variable region, disrupting structural stability, protein–protein interaction [ 24 ], and catalytic activity [ 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

Computational Insights into the Deleterious Impacts of Missense Variants on N-Acetyl-d-glucosamine Kinase Structure and Function

Dash

Mitra

Munni

et al. 2021

IJMS

View full text Add to dashboard Cite

An enzyme of the mammalian amino-sugar metabolism pathway, N-acetylglucosamine kinase (NAGK), that synthesizes N-acetylglucosamine (GlcNAc)-6-phosphate, is reported to promote dynein functions during mitosis, axonal and dendritic growth, cell migration, and selective autophagy, which all are unrelated to its enzyme activity. As non-enzymatic structural functions can be altered by genetic variation, we made an effort in this study aimed at deciphering the pathological effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in NAGK gene. An integrated computational approach, including molecular dynamics (MD) simulation and protein–protein docking simulation, was used to identify the damaging nsSNPs and their detailed structural and functional consequences. The analysis revealed the four most damaging variants (G11R, G32R, G120E, and A156D), which are highly conserved and functional, positioned in both small (G11R and G32R) and large (G120E and A156D) domains of NAGK. G11R is located in the ATP binding region, while variants present in the large domain (G120E and A156D) were found to induce substantial alterations in the structural organizations of both domains, including the ATP and substrate binding sites. Furthermore, all variants were found to reduce binding energy between NAGK and dynein subunit DYNLRB1, as revealed by protein–protein docking and MM-GBSA binding energy calculation supporting their deleteriousness on non-canonical function. We hope these findings will direct future studies to gain more insight into the role of these variants in the loss of NAGK function and their role in neurodevelopmental disorders.

show abstract

“…Considering the above-mentioned facts, we performed extensive screening for the most damaging missense SNPs in MCM6 gene to identify the pathogenic SNPs. The MCM6 gene was extracted from the NCBI database and screened for high-risk pathogenicity using multiple bioinformatics tools with the highest precision level 27 – 29 . In addition, the mechanism by which pathogenic missense SNPs alter protein structure and function was also explored.…”

Section: Introductionmentioning

confidence: 99%

In silico functional, structural and pathogenicity analysis of missense single nucleotide polymorphisms in human MCM6 gene

Kamal,

Mia,

Faruque

et al. 2024

Sci Rep

View full text Add to dashboard Cite

Single nucleotide polymorphisms (SNPs) are one of the most common determinants and potential biomarkers of human disease pathogenesis. SNPs could alter amino acid residues, leading to the loss of structural and functional integrity of the encoded protein. In humans, members of the minichromosome maintenance (MCM) family play a vital role in cell proliferation and have a significant impact on tumorigenesis. Among the MCM members, the molecular mechanism of how missense SNPs of minichromosome maintenance complex component 6 (MCM6) contribute to DNA replication and tumor pathogenesis is underexplored and needs to be elucidated. Hence, a series of sequence and structure-based computational tools were utilized to determine how mutations affect the corresponding MCM6 protein. From the dbSNP database, among 15,009 SNPs in the MCM6 gene, 642 missense SNPs (4.28%), 291 synonymous SNPs (1.94%), and 12,500 intron SNPs (83.28%) were observed. Out of the 642 missense SNPs, 33 were found to be deleterious during the SIFT analysis. Among these, 11 missense SNPs (I123S, R207C, R222C, L449F, V456M, D463G, H556Y, R602H, R633W, R658C, and P815T) were found as deleterious, probably damaging, affective and disease-associated. Then, I123S, R207C, R222C, V456M, D463G, R602H, R633W, and R658C missense SNPs were found to be highly harmful. Six missense SNPs (I123S, R207C, V456M, D463G, R602H, and R633W) had the potential to destabilize the corresponding protein as predicted by DynaMut2. Interestingly, five high-risk mutations (I123S, V456M, D463G, R602H, and R633W) were distributed in two domains (PF00493 and PF14551). During molecular dynamics simulations analysis, consistent fluctuation in RMSD and RMSF values, high Rg and hydrogen bonds in mutant proteins compared to wild-type revealed that these mutations might alter the protein structure and stability of the corresponding protein. Hence, the results from the analyses guide the exploration of the mechanism by which these missense SNPs of the MCM6 gene alter the structural integrity and functional properties of the protein, which could guide the identification of ways to minimize the harmful effects of these mutations in humans.

show abstract

In silico screening and identification of deleterious missense SNPs along with their effects on CD-209 gene: An insight to CD-209 related-diseases

Cited by 8 publications

References 43 publications

An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene

An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene

Computational Insights into the Deleterious Impacts of Missense Variants on N-Acetyl-d-glucosamine Kinase Structure and Function

In silico functional, structural and pathogenicity analysis of missense single nucleotide polymorphisms in human MCM6 gene

Contact Info

Product

Resources

About