Identification of Damaging ns<scp>SNV</scp>s in Human<scp>ERCC</scp>2 Gene

Fang, Shuo; Zhang, Yuntong; Xu, Miao; Xue, Chunyu; Xing, Xin

doi:10.1111/cbdd.12772

Cited by 5 publications

(7 citation statements)

References 48 publications

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“…Unfortunately, the various association studies on rs1800629 have obtained conflicting results due to their relative small sample size (Deepika et al 2013;Kume et al 2016). Furthermore, rs4645843, giving rise to a Pro-to-Leu exchange at 84 position of TNF-α, has the greatest impact on the TNF-α protein structure stability based on the in silico analysis (Dabhi and Mistry 2014;Fang et al 2016). However, this variant in TNF-α has never been investigated in the association study of PCOS.…”

Section: Discussionmentioning

confidence: 99%

A Missense Variant rs4645843 in TNF-α Gene Is a Risk Factor of Polycystic Ovary Syndrome in the Uygur Population

Zhao

Wan

2017

Tohoku J. Exp. Med.

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Polycystic ovary syndrome (PCOS) is a complex endocrine syndrome, resulting from the interaction of gene variants and environmental factors. PCOS is viewed as a proinflammatory state and is characterized by hyperandrogenism, hyperinsulinemia, and over-weight. In China, the incidence of PCOS is higher in the Uygur population than that in the Chinese Han population. The association of the tumor necrosis factor α (TNF-α ) gene with PCOS remains to be clarified. Here, we investigated the association of TNF-α polymorphisms with PCOS in the Uygur population (393 patients with PCOS and 381 healthy subjects). Two single-nucleotide polymorphisms in TNF-α were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method: rs1800629 (-308G/A polymorphism), a commonly tested variant and rs4645843 (6213C/T polymorphism) that causes a Pro-to-Leu substitution at position 84, the most damaging variant of TNF-α based on in silico analysis. We thus found that both the genotypic and allelic distributions of rs4645843 were significantly different between PCOS and control groups (p = 0.03 and 0.024, respectively), whereas those of rs1800629 were similar between the groups. Furthermore, rs4645843 was significantly associated with serum testosterone levels and the score of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), but no such association was found with rs1800629. Importantly, both rs4645843 and rs1800629 were significantly associated with higher body mass index (p < 0.05). This is the first study that shows the association of TNF-α gene with PCOS in the Uygur population. The TNF-α gene may influence the pathogenesis of PCOS through regulating testosterone level, obesity and HOMA-IR.

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Section: Discussionmentioning

confidence: 99%

A Missense Variant rs4645843 in TNF-α Gene Is a Risk Factor of Polycystic Ovary Syndrome in the Uygur Population

Zhao

Wan

2017

Tohoku J. Exp. Med.

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“…However, it is not feasible to perform costly population‐based genotyping to identify possible disease‐causing SNVs or drug targets . Fang et al . proposed a new strategy to identify potential disease‐causing SNVs by studying possible functional nsSNVs in genes.…”

Section: Discussionmentioning

confidence: 99%

“…Inconsistent analysis results were reported when using different tools that have their own inherent strengths and weaknesses; hence, the overlap of results from multiple tools has attracted more attention to develop a more reliable method for the analysis of nsSNVs . Fang et al . recently proposed a new strategy for finding useful information on drug development through the studying of possible functional SNVs in a certain gene.…”

Section: Introductionmentioning

confidence: 99%

Deleterious effects of non‐synonymous single nucleotide variants of human IL‐1β gene

et al. 2017

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The IL-1β gene is currently topic of interest for its important role in the pathogenesis of intervertebral disk degeneration. The new sequencing technology makes it crucial to study the effects of variants in IL-1β. Thus, 714 IL-1β variants with evidence supporting were collected from the EMBL database. Among them, 62 were non-synonymous single nucleotide variants (nsSNVs). Furthermore, six common nsSNVs were predicted to have damaging effects by SIFT, PolyPhen, PROVEAN and SNPs&GO. Based on the constructed three-dimensional structure of pro-IL-1β, rs375479974 with a mutation of Phe to Ser was proposed to reduce the stability of the pro-IL-1β protein. The rs375479974 variant was found to cause least common stabilizing amino acid residues, decrease hydrophilic and increase hydrophobic surface areas in the greatest degree, and have the lowest free energy alterations in I-Mutant 2.0 sequence analysis. When analyzing the interaction between the experimental 3D structure of mature IL-1β and its neutralizing McAb canakinumab complex, the rs775174784 substitution of Leu with Phe was found to attenuate this interaction by reducing binding energy, while rs375479974 not. Molecular dynamics simulation results in intervertebral disk environment supported rs775174784's effects. These results suggest that both rs375479974 and rs775174784 may have potential clinical and drug target implications.

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“…Based on the lentiviral vector construction method (Cai et al 2010;Fang et al 2016), the pGCSIL-hU6.flag-hSLC24A2.CMV. eGFP, pGCSIL-hU6.flag-hSLC24A2mu.CMV.eGFP, and pGCSIL-hU6.mock.CMV.eGFP were constructed.…”

Section: Vector Constructionmentioning

confidence: 99%

“…Various factors can cause the late diagnosis of PDAC, such as rapid local growth and metastasis of tumor cells, the high rate of recur rence, and resistance to chemotherapy or radiotherapy (Maitra and Hruban 2008). Thus, exploring the possible biomarkers for the early diagno sis and therapy of PDAC seems extremely urgent (Fang et al 2016).…”

Section: Introductionmentioning

confidence: 99%

A SLC24A2 Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing

Wang

Shao

Chen

et al. 2017

Tohoku J. Exp. Med.

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Pancreatic ductal adenocarcinoma (PDAC) presents as an aggressive malignancy caused by environmental and genetic factors. In order to identify causal genes for PDAC, we performed whole exome sequencing (WES) to detect gene mutations in seven pairs of PDAC tissue and adjacent non-tumor tissue samples. Finally, we found a new nonsynonymous single nucleotide variant (nsSNV) in solute carrier 24 family member 2 (SLC24A2) gene resulting in the substitution of native glutamic acid (E) into aspartic acid (D) at position of 287 amino acid (E287D) in SLC24A2 protein, and confirmed this variant by Sanger gene sequencing. SLC24A2 is a potassium-dependent sodium-calcium exchanger and can transport metal ion across cell membrane. Multiple in silico variants' effects analyses methods including SIFT, PolyPhen, PROVEAN, and PANTHER demonstrated this variant had probably damaging effects, which was consistent with the results obtained from Mutation Taster software analysis with a probability of 0.99999997 to be "disease causing." The three dimension (3D) structure analysis results suggested this variant had little effects on the solubility and hydrophobicity of the protein; but it could decrease the protein stability by increasing the total protein structure energy (−8874.33 kJ/mol for the mutant and −8963.54 kJ/mol for the native) and by causing the mutant protein decreasing three stabilizing residues. Less stability of the mutant 287D protein than the native E287 protein was also supported by I-Mutant and Western-blotting analysis results. Overall, a new mutation in SLC24A2 gene was identified to decrease the stability of SLC24A2, which may have potential clinical usages.

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Identification of Damaging nsSNVs in HumanERCC2 Gene

Cited by 5 publications

References 48 publications

A Missense Variant rs4645843 in <i>TNF-</i><i>α</i> Gene Is a Risk Factor of Polycystic Ovary Syndrome in the Uygur Population

A Missense Variant rs4645843 in <i>TNF-</i><i>α</i> Gene Is a Risk Factor of Polycystic Ovary Syndrome in the Uygur Population

Deleterious effects of non‐synonymous single nucleotide variants of human IL‐1β gene

A <i>SLC24A2</i> Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing

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