A polymorphism rs3746444 within the pre‐miR‐499 alters the maturation of miR‐499‐5p and its antiapoptotic function

Ding, Wei; Li, Mengyang; Sun, Tao; Han, Dongyi; Guo, Xiaoci; Chen, Xiao; Wan, Qinggong; Zhang, Xuejuan; Jx, Wang

doi:10.1111/jcmm.13813

Cited by 14 publications

(20 citation statements)

References 53 publications

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“…In our study, the miRNAs harboring variants showed remarkable alterations in their secondary structures, and this may have affected the expression profile of miRNAs in the plasma of patients with RASopathies. This fact has already been observed in selected miRNA variants, including processing and/or target recognition by miRNAs in rs3746444 located within the pre-miR-499, affecting the maturing of miR-499-5p, and interfering in the antiapoptotic function by converting stable A-U base pair to wobble G-U base pair in pre-miR-499 secondary structure (Ding et al, 2018). Another study showed that rs11614913 in the miR-196a2 sequence could alter mature expression and target mRNA binding (Xu et al, 2009).…”

Section: Discussionmentioning

confidence: 73%

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

et al. 2019

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RASopathies are a group of rare genetic diseases caused by germline mutations in genes involved in the RAS–mitogen-activated protein kinase (RAS-MAPK) pathway. Whole-exome sequencing (WES) is a powerful approach for identifying new variants in coding and noncoding DNA sequences, including miRNAs. miRNAs are fine-tuning negative regulators of gene expression. The presence of variants in miRNAs could lead to malfunctions of regulation, resulting in diseases. Here, we identified 41 variants in mature miRNAs through WES analysis in five patients with previous clinical diagnosis of RASopathies syndromes. The pathways, biological processes, and diseases that were over-represented among the target genes of the mature miRNAs harboring variants included the RAS, MAPK, RAP1, and PIK3-Akt signaling pathways, neuronal differentiation, neurogenesis and nervous system development, congenital cardiac defects (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy), and the phenotypes and syndromes of RASopathies (Noonan syndrome, Legius syndrome, Costello syndrome, Cafe au lait spots multiple, subaortic stenosis, pulmonary valve stenosis, and LEOPARD syndrome). Furthermore, eight selected variants in nine mature miRNAs (hsa-miR-1304, hsa-miR-146a, hsa-miR-196a2, hsa-miR-499a/hsa-miR-499b, hsa-miR-449b, hsa-miR-548l, hsa-miR-575, and hsa-miR-593) may have caused alterations in the secondary structures of miRNA precursor. Selected miRNAs containing variants such as hsa-miR-146a-3p, hsa-miR-196a-3p, hsa-miR-548l, hsa-miR-449b-5p, hsa-miR-575, and hsa-miR499a-3p could regulate classical genes associated with Rasopathies and RAS-MAPK pathways, contributing to modify the expression pattern of miRNAs in patients. RT-qPCR expression analysis revealed four differentially expressed miRNAs that were downregulated: miRNA-146a-3p in P1, P2, P3, P4, and P5, miR-1304-3p in P2, P3, P4, and P5, miR-196a2-3p in P3, and miR-499b-5p in P1. miR-499a-3p was upregulated in P1, P3, and P5. These results indicate that miRNAs show different expression patterns when these variants are present in patients. Therefore, this study characterized the role of miRNAs harboring variants related to RASopathies for the first time and indicated the possible implications of these variants for phenotypes of RASopathies such as congenital cardiac defects and cardio-cerebrovascular diseases. The expression and existence of miRNA variants may be used in the study of biomarkers of the RASopathies.

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Section: Discussionmentioning

confidence: 73%

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

et al. 2019

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“…Rs3746444 SNP is located on miR-499a-3p mature and the variant allele might affect its ability to suppress Drp1 and mitochondrial fission. Indeed, a recent in vitro study demonstrated that in cells transfected with pri-miR-499a carrying the variant allele, a minor reduction of its target, CnA, was observed than that in those transfected with pri-miR-499a carrying the wild-type allele (Ding et al, 2018). The correlation between the rs3746444 homozygous variant genotype and reduced mtDNA copy number could also explain the higher DN risk associated with the variant allele of this miRNA gene, which we had described in our previous article (Ciccacci et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Copy Number in Peripheral Blood Is Reduced in Type 2 Diabetes Patients with Polyneuropathy and Associated with a MIR499A Gene Polymorphism

Latini

Borgiani

Benedittis

et al. 2020

DNA and Cell Biology

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Our aim was to evaluate in a cohort of 125 Italian patients with type 2 diabetes (T2D), who underwent neurological evaluation, the possible differences in the number of mitochondrial DNA copies (mtDNA) comparing positive and negative patients for cardiovascular autonomic neuropathy (CAN) or diabetic peripheral neuropathy (DPN) and comparing them with healthy controls. We also investigated a possible correlation of the number of mtDNA copies with the polymorphism rs3746444 of the MIR499A. T2D patients show a decrease in the number of mtDNA copies compared to healthy controls (p = 2 • 10-10). Dividing the T2D subjects by neurological evaluation, we found a significant mtDNA decrease in patients with DPN compared with those without (p = 0.02), while no differences were observed between subjects with and without CAN. Furthermore, the homozygous variant genotype for the polymorphism rs3746444 of MIR499A correlates with a decrease in the number of mtDNA copies, particularly in T2D patients (p = 0.009). Our data show a decrease in the number of mtDNA copies in subjects with T2D and suggest that this decrease is more evident in patients who develop DPN. Furthermore, the association of the variant allele of MIR499A with the number of mtDNA copies allows us to hypothesize a possible effect of this polymorphism in oxidative stress.

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“…MicroRNA-499 rs3746444 has been proved to be signi cantly associated with increased risk of cancer of the respiratory system, digestive system,urinary system and gynecological system [42][43][44][45][46][47][48][49][50][51][52][53].Existing studies have been veri ed that the MiRNA-499(rs3746444 T > C) gene polymorphism can control the expression level of SOX gene. Due to the up-regulation of SOX6 gene, the anti-apoptosis function of MiRNA-499(rs3746444 T > C) can be reversed [54].…”

Section: Discussionmentioning

confidence: 99%

Association of rs3746444 in MiRNA-499 and rs3787016 in Long Non-coding RNAs POLR2E with Prostate Cancer: an updated meta-analysis and systematic review

Liu

Wang

et al. 2020

Preprint

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Background It has been proved that a significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Micro-RNAs and Long Non-coding RNAs are a group of a noncoding small molecule, which play critical roles in signalling pathways, metabolism, apoptosis and cancer development. Exercising a meta-analysis to examine the relationship between rs3746444, rs3787016 and prostate cancer (PCa) risk was the main objective of our study. Results 10 case-control studies were included, while 6 on rs3787016 and 4 on rs3746444. On the whole, the genotypes carrying the T allele, in which were verified an increased risk between rs3787016 and PCa risk.( T vs C: odds ratio(OR) = 1.802, 95% CI 1.015–3.198, P value of heterogeneity(PH) = 0.00%; CT vs CC: OR = 1.179,95% CI 1.091–1.275, PH = 0.41; TT vs CC: .OR = 1.418, 95% CI 1.229–1.636, PH= 0.961; TT + CT vs CC: OR = 1.216, 95% CI 1.129–1.310, PH= 0.408; TT vs CT + CC: OR = 1.328, 95%CI 1.159–1.521, PH = 0.987). A vital relevance was performed by this meta-analysis in three models between rs3746444 and PCa risk, in which a tendency of increased PCa risk could be found (C vs T: OR = 1.197, 95% CI 1.035–1.384, PH= 0.837; CC vs TT: OR = 1. 137, 95% CI 0.813–1.590, PH = 0.392; CC + CT vs TT: OR = 1.426, 95% CI 1.166–1.743, PH= 0.406.). Conclusion Our findings proposed that rs3746444 in MiRNA-499 and rs3787016 in Long Non-coding RNAs POLR2E polymorphisms increased the risk of developing PCa. Further functional studies are warranted to reveal the role of the polymorphism in carcinogenesis.

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A polymorphism rs3746444 within the pre‐miR‐499 alters the maturation of miR‐499‐5p and its antiapoptotic function

Cited by 14 publications

References 53 publications

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

Mitochondrial DNA Copy Number in Peripheral Blood Is Reduced in Type 2 Diabetes Patients with Polyneuropathy and Associated with a MIR499A Gene Polymorphism

Association of rs3746444 in MiRNA-499 and rs3787016 in Long Non-coding RNAs POLR2E with Prostate Cancer: an updated meta-analysis and systematic review

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