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Journal ArticleDOI

Identification and in silico analysis of functional SNPs of the BRCA1 gene.

01 Oct 2007-Genomics (Academic Press)-Vol. 90, Iss: 4, pp 447-452
TL;DR: It is proposed that an nsSNP (rs1800751) could be an important candidate for the breast cancer caused by the BRCA1 gene from a comparison of the stabilizing residues of the native and mutant proteins.
About: This article is published in Genomics.The article was published on 2007-10-01 and is currently open access. It has received 79 citations till now. The article focuses on the topics: Nonsynonymous substitution & Untranslated region.
Citations
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Journal ArticleDOI
01 Apr 2009-Eye
TL;DR: The authors' data constitute the first report of a heterozygous Q455V mutation of the COL8A2 gene in Korean patients with FECD, which may be the causative defect in the development and progression of Korean FECD patients.
Abstract: To investigate the possibility of collagen type VIII α2 (COL8A2) as a potential susceptibility gene for Korean patients with Fuchs' corneal dystrophy (FECD), we performed mutation screening of the COL8A2 gene. A total of 25 FECD patients were screened, including 15 patients from six pedigrees with early onset FECD and an additional 10 unrelated patients, all of Korean ancestry. Seventy-three control individuals without corneal disease were selected from the general population. PCR—SSCP and direct sequencing were used to screen genetic variations in COL8A2. The pathogenic impact of these sequence variants was evaluated through the SIFT and PolyPhen algorithms. We have identified a novel heterozygous mutation, Q455V, in exon 2 of COL8A2. All patients of Korean pedigrees with FECD had the Q455V mutation, and two out of nine unrelated cases also had this mutation. But it was not present in unaffected individuals from these pedigrees or from control groups. Two heterozygous missense mutations, R155Q and T502M, were also observed, but, they showed no significant difference between FECD patients and controls. The allele frequencies of A35A and G495G, which were synonymous substitutions, were significantly associated with FECD. Both Q455V and T502M were predicted as deleterious mutations by computational methods using PolyPhen and SIFT. Our data constitute the first report of a heterozygous Q455V mutation of the COL8A2 gene in Korean patients with FECD. Q455V may be the causative defect in the development and progression of Korean FECD patients.

66 citations

Journal ArticleDOI
25 Oct 2012-Gene
TL;DR: In silico analysis suggested that S136A and P764L variants of BRAF could directly or indirectly destabilize the amino acid interactions and hydrogen bond networks thus explain the functional deviations of protein to some extent.

59 citations

Journal ArticleDOI
TL;DR: A comprehensive analysis of the functional and structural impact of all known SNPs in this gene using publicly available computational prediction tools shows that a mutation from arginine to cysteine at position 1216 on the surface of the protein caused the greatest impact on stability.
Abstract: Insulin-like growth factor 1 receptor (IGF1R) acts as a critical mediator of cell proliferation and survival. Many single nucleotide polymorphisms (SNPs) found in the IGF1R gene have been associated with various diseases, including both breast and prostate cancer. The genetics of these diseases could be better understood by knowing the functions of these SNPs. In this study, we performed a comprehensive analysis of the functional and structural impact of all known SNPs in this gene using publicly available computational prediction tools. Out of a total of 2412 SNPs in IGF1R retrieved from dbSNP, we found 32 nsSNPs, 58 sSNPs, 83 mRNA 3' UTR SNPs, and 2225 intronic SNPs. Among the nsSNPs, a total of six missense nsSNPs were found to be damaging by both a sequence homology-based tool (SIFT) and a structural homology-based method (PolyPhen), and one nonsense nsSNP was found. Further, we modeled mutant proteins and compared the total energy values with the native IGF1R protein, and showed that a mutation from arginine to cysteine at position 1216 (rs61740868) on the surface of the protein caused the greatest impact on stability. Also, the FASTSNP tool suggested that 31 sSNPs and 3 intronic SNPs might affect splicing regulation. Based on our investigation, we report potential candidate SNPs for future studies on IGF1R mutations.

50 citations

Journal ArticleDOI
TL;DR: This study suggests that the four mutations might affect thePRPS1 protein function and stability of the structure, and may serve as a platform for drug repositioning and personalized medicine for diseases that are caused by the PRPS1 deficiency.
Abstract: Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited congenital neurological disorders, affecting approximately 1 in 2500 in the US. About 80 genes were found to be in association with CMT. The phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is an essential enzyme in the primary stage of de novo and salvage nucleotide synthesis. The mutations in the PRPS1 gene leads to X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), PRS super activity, Arts syndrome, X-linked deafness-1, breast cancer, and colorectal cancer. In the present study, we obtained 20 missense mutations from UniProt and dbSNP databases and applied series of comprehensive in silico prediction methods to assess the degree of pathogenicity and stability. In silico tools predicted four missense mutations (D52H, M115 T, L152P, and D203H) to be potential disease causing mutations. We further subjected the four mutations along with native protein to 50 ns molecular dynamics simulation (MDS) using Gromacs package. The resulting trajectory files were analyzed to understand the stability differences caused by the mutations. We used the Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), solvent accessibility surface area (SASA), Covariance matrix, Principal Component Analysis (PCA), Free Energy Landscape (FEL), and secondary structure analysis to assess the structural changes in the protein upon mutation. Our study suggests that the four mutations might affect the PRPS1 protein function and stability of the structure. The proposed study may serve as a platform for drug repositioning and personalized medicine for diseases that are caused by the PRPS1 deficiency.

48 citations


Cites background from "Identification and in silico analys..."

  • ...…and demonstrated their potential effect on protein structure, function, and stability (Sang et al. 2016; Agrahari and George Priya Doss 2015; Bhardwaj et al. 2016; Tekcan 2016; Bakhit et al. 2016; Rajasekaran et al. 2007; Doss and Sethumadhavan 2009; Zaki et al. 2017a, b; Mosaeilhy et al. 2017)....

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Journal ArticleDOI
Brijesh Dabhi1, Kinnari N. Mistry1
TL;DR: It is suggested that P84L and A94T variants of TNF-α could directly or indirectly destabilize the amino acid interactions and hydrogen bond networks thus explaining the functional deviations of protein to some extent.

48 citations


Cites methods from "Identification and in silico analys..."

  • ...Similar approach has been used to investigate the effect of nsSNP of BARD1gene and BRCA1 gene (Ali et al., 2012; Rajasekaran et al., 2007)....

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References
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Journal ArticleDOI
TL;DR: The dbSNP database is a general catalog of genome variation to address the large-scale sampling designs required by association studies, gene mapping and evolutionary biology, and is integrated with other sources of information at NCBI such as GenBank, PubMed, LocusLink and the Human Genome Project data.
Abstract: In response to a need for a general catalog of genome variation to address the large-scale sampling designs required by association studies, gene mapping and evolutionary biology, the National Center for Biotechnology Information (NCBI) has established the dbSNP database [S.T.Sherry, M.Ward and K.Sirotkin (1999) Genome Res., 9, 677–679]. Submissions to dbSNP will be integrated with other sources of information at NCBI such as GenBank, PubMed, LocusLink and the Human Genome Project data. The complete contents of dbSNP are available to the public at website: http://www.ncbi.nlm.nih.gov/SNP. The complete contents of dbSNP can also be downloaded in multiple formats via anonymous FTP at ftp:// ncbi.nlm.nih.gov/snp/.

6,449 citations


"Identification and in silico analys..." refers methods in this paper

  • ...The SNPs and their related protein sequence for the BRCA1 gene were obtained from the dbSNP [8] (http://www....

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  • ...The BRCA1 gene investigated in this work was retrieved from the dbSNP database [8]....

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Journal ArticleDOI
07 Oct 1994-Science
TL;DR: A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods.
Abstract: A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

6,118 citations

Journal ArticleDOI
TL;DR: SIFT is a program that predicts whether an amino acid substitution affects protein function so that users can prioritize substitutions for further study and can distinguish between functionally neutral and deleterious amino acid changes in mutagenesis studies and on human polymorphisms.
Abstract: Single nucleotide polymorphism (SNP) studies and random mutagenesis projects identify amino acid substitutions in protein-coding regions. Each substitution has the potential to affect protein function. SIFT (Sorting Intolerant From Tolerant) is a program that predicts whether an amino acid substitution affects protein function so that users can prioritize substitutions for further study. We have shown that SIFT can distinguish between functionally neutral and deleterious amino acid changes in mutagenesis studies and on human polymorphisms. SIFT is available at http://blocks.fhcrc.org/sift/SIFT.html.

5,318 citations


"Identification and in silico analys..." refers background or methods in this paper

  • ...We used the program SIFT [9] available at http://blocks....

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  • ...Hence, changes at well-conserved positions tend to be predicted as deleterious [9]....

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  • ...The conservation level of a particular position in a protein was determined by using a sequence homology-based tool, SIFT [9]....

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Journal ArticleDOI
TL;DR: Disruption of the estrogen receptor in humans need not be lethal and is important for bone maturation and mineralization in men as well as women.
Abstract: Background and Methods Mutations in the estrogen-receptor gene have been thought to be lethal. A 28-year-old man whose estrogen resistance was caused by a disruptive mutation in the estrogen-receptor gene underwent studies of pituitary-gonadal function and bone density and received transdermal estrogen for six months. Estrogen-receptor DNA, extracted from lymphocytes, was evaluated by analysis of single-strand-conformation polymorphisms and by direct sequencing. Results The patient was tall (204 cm [80.3 in.]) and had incomplete epiphyseal closure, with a history of continued linear growth into adulthood despite otherwise normal pubertal development. He was normally masculinized and had bilateral axillary acanthosis nigricans. Serum estradiol and estrone concentrations were elevated, and serum testosterone concentrations were normal. Serum follicle-stimulating hormone and luteinizing hormone concentrations were increased. Glucose tolerance was impaired, and hyperinsulinemia was present. The bone mineral d...

2,443 citations


"Identification and in silico analys..." refers background in this paper

  • ...Also, nsSNPs affect the functional roles of proteins in the signal transduction of visual, hormonal, and other stimulants [5,6]....

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Journal ArticleDOI
TL;DR: A tool that uses sequence homology to predict whether a substitution affects protein function is constructed, which may be used to identify plausible disease candidates among the SNPs that cause missense substitutions.
Abstract: Many missense substitutions are identified in single nucleotide polymorphism (SNP) data and large-scale random mutagenesis projects. Each amino acid substitution potentially affects protein function. We have constructed a tool that uses sequence homology to predict whether a substitution affects protein function. SIFT, which sorts intolerant from tolerant substitutions, classifies substitutions as tolerated or deleterious. A higher proportion of substitutions predicted to be deleterious by SIFT gives an affected phenotype than substitutions predicted to be deleterious by substitution scoring matrices in three test cases. Using SIFT before mutagenesis studies could reduce the number of functional assays required and yield a higher proportion of affected phenotypes. may be used to identify plausible disease candidates among the SNPs that cause missense substitutions.

2,374 citations


"Identification and in silico analys..." refers background in this paper

  • ...Substitutions at each position with normalized probabilities less than a chosen cutoff are predicted to be deleterious and those greater than or equal to the cutoff are predicted to be tolerated [10]....

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