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

Rajasekaran, R.; Sudandiradoss, C.; Doss, C. George Priya; Sethumadhavan, Rao

doi:10.1016/j.ygeno.2007.07.004

Cited by 81 publications

(56 citation statements)

References 25 publications

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“…Our study may suggest an alternative mutational mechanism because four patients without structural abnormality of BRCA1 or BRCA2 showed AI at transcribed polymorphisms, thereby suggesting the disruption of longdistance cis-regulatory elements 35,36 or mutations in the 3 0 -UTR that influence RNA half-life. 37 It is worth noting that these four patients have a high probability of bearing a mutation at a general autosomal dominant breast cancer susceptibility locus that is, 48 -89% depending on the case, and according to the Claus model modified by Easton. 15 However, all belong to female breast cancer-only families.…”

Section: Discussionmentioning

confidence: 99%

Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study

et al. 2009

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Nearly one-half of BRCA1 and BRCA2 sequence variations are variants of uncertain significance (VUSs) and are candidates for splice alterations for example, by disrupting/creating splice sites. As out-of-frame splicing defects lead to a marked reduction of the level of the mutant mRNA cleared through nonsense-mediated mRNA decay, a cDNA-based test was developed to show the resulting allelic imbalance (AI). Fifty-four VUSs identified in 53 hereditary breast/ovarian cancer (HBOC) patients without BRCA1/2 mutation were included in the study. Two frequent exonic single-nucleotide polymorphisms on both BRCA1 and BRCA2 were investigated by using a semiquantitative single-nucleotide primer extension approach and the cDNA allelic ratios obtained were corrected using genomic DNA ratios from the same sample. A total of five samples showed AI. Subsequent transcript analyses ruled out the implication of VUS on AI and identified a deletion encompassing BRCA2 exons 12 and 13 in one sample. No sequence abnormality was found in the remaining four samples, suggesting implication of cis-or trans-acting factors in allelic expression regulation that might be disease causative in these HBOC patients. Overall, this study showed that AI screening is a simple way to detect deleterious splicing defects and that a major role for VUSs and deep intronic mutations in splicing anomalies is unlikely in BRCA1/2 genes. Methods to analyze gene expression and identify regulatory elements in BRCA1/2 are now needed to complement standard approaches to mutational analysis.

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Section: Discussionmentioning

confidence: 99%

Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study

et al. 2009

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“…[22][23][24][25] The SIFT programme was applied to prioritize three missense mutations in the exon 2 coding region of COL8A2. The tolerance index score for each mutation was 0.00, predicting a deleterious effect for each.…”

Section: Discussionmentioning

confidence: 99%

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

Mok

Kim

Joo

2008

Eye

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Purpose To investigate the possibility of collagen type VIII a2 (COL8A2) as a potential susceptibility gene for Korean patients with Fuchs' corneal dystrophy (FECD), we performed mutation screening of the COL8A2 gene. Methods 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. PCRFSSCP 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.Results 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. Conclusions 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.

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“…For a given amino acid substitution in a protein, PolyPhen-2 extracts various sequence and structure-based features of the substitution site and feeds them to a probabilistic classifier. [23] …”

Section: In Silico Analysismentioning

confidence: 99%

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Abilash

2017

AJP

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Introduction: Adipose tissue is an endocrine organ which is made up of special connective tissue. The major task of this tissue is to accumulate the energy in the form of triacylglycerol (TAG). Adipogenesis is the process of formation of the preadipocyte into the mature adipocyte. Normally adipose tissue is of two types, namely, white adipose tissue (WAT) and brown adipose tissue (BAT). An important role WAT is to store TAG and the significant responsibility BAT is production of heat (thermogenesis). Fat accumulation is identified by the balance between the fat synthesis such as adipogenesis and the fat break down such as lipolysis. When there is excessive amount of intake of food, elevated plasma carbohydrate and triglyceride are involved in lipogenesis in adipose tissue. During fasting condition, there is a process called lipolysis which releases fatty acids and glycerol into the circulation. Our aim is to investigate the single nucleotide polymorphisms (SNP) analysis of genes participated in maintenance of adipose tissue such as hormone sensitive lipase monoglyceride lipase and adiponectin. Materials and Methods: In silico analysis using sorting intolerant from tolerant (SIFT), polyphen 2 was performed for the genes concerned in maintaining adipose tissue homeostasis. Results: SNPs were analyzed for all the genes. Benign and damaging SNPs were identified using SIFT and polyphen 2. Conclusion: As SNPs show suppressed stability, damaging and benign character, they can be further utilized for in vivo studies to determine the role of these genes in adipose tissue homeostasis.

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

Cited by 81 publications

References 25 publications

Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study

Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

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