Computational analysis for the determination of deleterious nsSNPs in human MTHFD1 gene

Desai, Mansi; Chauhan, Jenabhai B.

doi:10.1016/j.compbiolchem.2017.07.001

Cited by 20 publications

(13 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, Dakal et al . used PROVEAN, PolyPhen2, and SIFT to predict the functional effects of aa variants in the interleukin 8 gene [ 92 ], whereas Desai et al utilized the same tools to identify deleterious variants in methylenetetrahydrofolate dehydrogenase 1 [ 93 ]. The prediction tool predicts whether the aa variant is likely to have an effect in protein function or not [ 65 , 69 , 94 ].…”

Section: Discussionmentioning

confidence: 99%

In Silico Analysis of Hepatitis B Virus Occult Associated Mutations in Botswana Using a Novel Algorithm

Anderson

Choga

Moyo

et al. 2018

Genes

View full text Add to dashboard Cite

Occult hepatitis B infections (OBI) represent a reservoir of undiagnosed and untreated hepatitis B virus (HBV), hence the need to identify mutations that lead to this phenotype. Functionally characterizing these mutations by in vitro studies is time-consuming and expensive. To bridge this gap, in silico approaches, which predict the effect of amino acid (aa) variants on HBV protein function, are necessary. We developed an algorithm for determining the relevance of OBI-associated mutations using in silico approaches. A 3 kb fragment of subgenotypes A1 and D3 from 24 chronic HBV-infected (CHB) and 24 OBI participants was analyzed. To develop and validate the algorithm, the effects of 68 previously characterized occult-associated mutations were determined using three computational tools: PolyPhen2, SNAP2, and PROVEAN. The percentage of deleterious mutations (with impact on protein function) predicted were 52 (76.5%) by PolyPhen2, 55 (80.9%) by SNAP2, and 65 (95.6%) by PROVEAN. At least two tools correctly predicted 59 (86.8%) mutations as deleterious. To identify OBI-associated mutations exclusive to Botswana, study sequences were compared to CHB sequences from GenBank. Of the 43 OBI-associated mutations identified, 26 (60.5%) were predicted by at least two tools to have an impact on protein function. To our knowledge, this is the first study to use in silico approaches to determine the impact of OBI-associated mutations, thereby identifying potential candidates for functional analysis to facilitate mechanistic studies of the OBI phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

In Silico Analysis of Hepatitis B Virus Occult Associated Mutations in Botswana Using a Novel Algorithm

Anderson

Choga

Moyo

et al. 2018

Genes

View full text Add to dashboard Cite

show abstract

“…PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) is a web-based tool which predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations. [16] Three possible outcomes of mutations were predicted by PolyPhen-2: probably damaging, possibly damaging or benign according to the score ranging from 0 to 1.…”

Section: Methodsmentioning

confidence: 99%

Identification of a novel mutation of FGFR3 gene in a large Chinese pedigree with hypochondroplasia by next-generation sequencing

Yao

Wang

et al. 2019

Medicine

View full text Add to dashboard Cite

Rationale:Hypochondroplasia (HCH) is the mildest form of chondrodysplasia characterized by disproportionate short stature, short extremities, and variable lumbar lordosis. It is caused by mutations in fibroblast growth factor receptor 3 (FGFR3) gene. Up to date, at least thirty mutations of FGFR3 gene have been found to be related to HCH. However, mutational screening of the FGFR3 gene is still far from completeness. Identification of more mutations is particularly important in diagnosis of HCH and will gain more insights into the molecular basis for the pathogenesis of HCH.Patient concerns:A large Chinese family consisting of 53 affected individuals with HCH phenotypes was examined.Diagnoses:A novel missense mutation, c.1052C>T, in FGFR3 gene was identified in a large Chinese family with HCH. On the basis of this finding and clinical manifestations, the final diagnosis of HCH was made.Interventions:Next-generation sequencing (NGS) of DNA samples was performed to detect the mutation in the chondrodysplasia-related genes on the proband and her parents, which was confirmed by Sanger sequencing in the proband and most of other living affected family members.Outcomes:A novel missense mutation, c.1052C>T, in the extracellular, ligand-binding domain of FGFR3 was identified in a large Chinese family with HCH. This heterozygous mutation results in substitution of serine for phenylalanine at amino acid 351 (p.S351F) and co-segregates with the phenotype in this family. Molecular docking analysis reveals that this unique FGFR3 mutation results in an enhancement of ligand-binding affinity between FGFR3 and its main ligand, fibroblast growth factor 9.Lessons:This novel mutation is the first mutation displaying an increase in ligand-binding affinity, therefore it may serve as a model to investigate ligand-dependent activity of FGF-FGFR complex. Our data also expanded the mutation spectrum of FGFR3 gene and facilitated clinic diagnosis and genetic counseling for this family with HCH.

show abstract

“…Both non-coding and intergenic SNPs may have slight impact, but non-synonymous coding SNPs (nsSNPs) have more impact on protein [20]. Identification of the impact of variants on structure, stability and function of the protein is an important task as not all reported polymorphisms are deleterious [23]. Therefore there is a need to understand the deleterious impact of nsSNPs on protein structure and function using different recent molecular biology techniques.…”

Section: Introductionmentioning

confidence: 99%

Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact

2019

View full text Add to dashboard Cite

Nowadays CHK2 mutation is studied frequently in hereditary breast and ovarian cancer patients in addition to BRCA1/BRCA2. CHK2 is a tumor suppressor gene that encodes a serine/threonine kinase, also involved in pathways such as DNA repair, cell cycle regulation and apoptosis in response to DNA damage. CHK2 is a well-studied moderate penetrance gene that correlates with third high risk susceptibility gene with an increased risk for breast cancer. Hence before planning large population study, it is better to scrutinize putative functional SNPs of CHK2 using different computational tools. In this study, we have used various computational approaches to identify nsSNPs which are deleterious to the structure and/or function of CHK2 protein that might be causing this disease. Computational analysis was performed by different in silico tools including SIFT, Align GVGD, SNAP-2, PROVEAN, Poly-Phen-2, PANTHER, PhD-SNP, MUpro, iPTREE-STAB, Consurf, InterPro, NCBI Conserved Domain Search tool, ModPred, SPARKS-X, RAMPAGE, Verify-3D, FT Site, COACH and PyMol. Out of 78 nsSNP of human CHK2 gene, seven nsSNPs were predicted functionally most significant SNPs. Among these seven nsSNP, p.Arg160Gly, p.Gly210Arg and p.Ser415Phe are highly conserved residues with conservation score of 9 and three nsSNP were predicted to be involved in post translational modification. The p.Arg160Gly and p.Gly210Arg may interfere in phosphopeptide binding site on FHA conserved domain. The p.Ser415Phe may interfere in formation of activation loop of protein-kinase domain and might interfere in interactions of CHK2 with ligand. The study concludes that mutation of serine to phenylalanine at position 415 is a major mutation in native CHK2 protein which might contribute to its malfunction, ultimately causing disease. This is the first comprehensive study, where CHK2 gene variants are analyzed using in silico tools hence it will be of great help while considering large scale studies and also in developing precision medicines related to these polymorphisms in the era of personalized medicine.

show abstract

Computational analysis for the determination of deleterious nsSNPs in human MTHFD1 gene

Cited by 20 publications

References 37 publications

In Silico Analysis of Hepatitis B Virus Occult Associated Mutations in Botswana Using a Novel Algorithm

In Silico Analysis of Hepatitis B Virus Occult Associated Mutations in Botswana Using a Novel Algorithm

Identification of a novel mutation of FGFR3 gene in a large Chinese pedigree with hypochondroplasia by next-generation sequencing

Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact

Contact Info

Product

Resources

About