Association of the common SNPs in RNF212, STAG3 and RFX2 gene with male infertility with azoospermia in Chinese population

Yu, Cheng-He; Xie, Ting; Zhang, Ruo-Peng; Zhou-Cun, A

doi:10.1016/j.ejogrb.2017.12.030

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…Yu et al detected that the frequencies of allele C and the genotype CC at the rs4045481 locus in RNF212 gene were significantly higher in patients with azoospermia in comparison with controls. Furthermore, they reported that homozygous of allele C (genotype CC) may decrease the activity of pre-mRNA due to the disappearance of the binding motifs of SRSF5, leading to the reduced expression of RNF212 and influencing normal spermatogenesis, consequently increasing ther risk of azoospermia[40]. Nevertheless, we found that the increased expression of RNF212 exhibited a positive correlation with dorsopathies.…”

Section: Discussionmentioning

confidence: 54%

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Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

Cui,

Guo,

et al. 2024

Preprint

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Background Dorsopathies are a group of musculoskeletal disorders affecting the spinal column and related structures, contributing significantly to global disability rates and healthcare costs. Despite their prevalence, the genetic and biological mechanisms underlying dorsopathies are not fully understood. Method Summary-data-based Mendelian Randomization (SMR) and colocalization analysis were employed, using data from genome-wide association studies (GWAS) and cis-expression quantitative trait loci (cis-eQTLs) databases. Genes with a colocalization posterior probability (PP.H4) above 0.7 in SMR results were selected for additional analysis. These selected genes underwent MR analysis to examine possible causal connections with dorsopathies, and sensitivity analyses were carried out to ensure robustness. Additionally, two transcriptome-wide association studies (TWAS) were utilized to confirm and screen for potential drug targets. Result We identified four essential genes linked to dorsopathies: NLRC4, CGREF1, KHK, and RNF212. Mendelian randomization (MR) analysis revealed a potential causal link between these genes and dorsopathies. Elevated transcription levels of NLRC4, CGREF1, and KHK correlated with reduced dorsopathies risk, while increased levels of RNF212 were associated with heightened risk of dorsopathies. Regarding methylation sites, an increase in cg04686953 fully mediated the decreased risk of dorsopathies by RNF212. Similarly, the risk effect of cg26638505 and cg18948125 was entirely mediated by NLRC4, while CGREF1 predominantly mediated the risk-increasing effect of cg06112415 and the decrease effect of cg22740783. Conclusion Dorsopathies were associated with four pivotal genes: NLRC4, CGREF1, KHK, and RNF212. Methylation analysis identified cg04686953 and cg22740783 as protective against NPs risk, while cg26638505, cg18948125, and cg06112415 exhibited a risk-increasing impact.

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Section: Discussionmentioning

confidence: 54%

“…Regulatory factor X2 ( RFX2 ) gene is essential for maintaining normal spermatogenesis and involved in spermatogenesis impairment and male infertility in mice[40]. In particular, Ring finger protein 212 ( RNF212 ) gene is important for crossing over and chiasma formation during meiosis[41].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

Cui,

Guo,

et al. 2024

Preprint

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“…RFX2 can not only regulate ciliogenesis but also lead to left-right asymmetry through fluid flow in mice (Bisgrove et al, 2012). The deficiency of RFX2 in mouse testis leads to the difficulty of sperm flagellar production and the failure of spermatid to differentiate from round into elongated, resulting in spermatogenesis disorder and male sterility (Kistler et al, 2015;Wu et al, 2016;Yu et al, 2018). In rats, RFX2 binds to the H1t promoter, which is specifically expressed in testis and activate the transcription of H1t during spermatogenesis (Wolfe et al, 2006;Wolfe et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Molecular characteristics and transcriptional regulatory of spermatogenesis-related gene RFX2 in adult Banna mini-pig inbred line (BMI)

et al. 2023

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RFX2 plays critical roles in mammalian spermatogenesis and cilium maturation. Here, the testes of 12month-old adult boars of Banna mini-pig inbred line (BMI) were subjected to whole-transcriptome sequencing. The results indicated that the average expression (raw count) of RFX2 gene in BMI testes was 16138.25, and the average expression value of the corresponding transcript ENSSSCT00000043271.2 was 123.1898. The CDS of RFX2 obtained from BMI testes was 2,817 bp (GenBank accession number: OL362242). Gene structure analysis showed that RFX2 was located on chromosome 2 of the pig genome with 19 exons. Protein structure analysis indicated that RFX2 contains 728 amino acids with two conserved domains. Phylogenetic analysis revealed that RFX2 was highly conserved with evolutionary homologies among mammalian species. Other analyses, including PPI networks, KEGG, and GO, indicated that BMI RFX2 had interactions with 43 proteins involving various functions, such as in cell cycle, spermatid development, spermatid differentiation, cilium assembly, and cilium organization, etc. Correlation analysis between these proteins and the transcriptome data implied that RFX2 was significantly associated with FOXJ1, DNAH9, TMEM138, E2F7, and ATR, and particularly showed the highest correlation with ATR, demonstrating the importance of RFX2 and ART in spermatogenesis. Functional annotation implied that RFX2 was involved in 17 GO terms, including three cellular components (CC), six molecular functions (MF), and eight biological processes (BP). The analysis of miRNA-gene targeting indicated that BMI RFX2 was mainly regulated by two miRNAs, among which four lncRNAs and five lncRNAs competitively bound ssc-miR-365-5p and ssc-miR-744 with RFX2, respectively. Further, the dual-luciferase report assay indicated that the ssc-miR-365-5p and ssc-miR-744 significantly reduced luciferase activity of RFX2 3'UTR in the 293T cells, suggesting that these two miRNAs regulated the expression of RFX2. Our results revealed the important role of RFX2 in BMI spermatogenesis, making it an intriguing candidate for follow-up studies.

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Genetic Landscape of Nonobstructive Azoospermia and New Perspectives for the Clinic

Cerván-Martín

Castilla

Palomino-Morales

et al. 2020

JCM

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Nonobstructive azoospermia (NOA) represents the most severe expression of male infertility, involving around 1% of the male population and 10% of infertile men. This condition is characterised by the inability of the testis to produce sperm cells, and it is considered to have an important genetic component. During the last two decades, different genetic anomalies, including microdeletions of the Y chromosome, karyotype defects, and missense mutations in genes involved in the reproductive function, have been described as the primary cause of NOA in many infertile men. However, these alterations only explain around 25% of azoospermic cases, with the remaining patients showing an idiopathic origin. Recent studies clearly suggest that the so-called idiopathic NOA has a complex aetiology with a polygenic inheritance, which may alter the spermatogenic process. Although we are far from a complete understanding of the molecular mechanisms underlying NOA, the use of the new technologies for genetic analysis has enabled a considerable increase in knowledge during the last years. In this review, we will provide a comprehensive and updated overview of the genetic basis of NOA, with a special focus on the possible application of the recent insights in clinical practice.

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Association of the common SNPs in RNF212, STAG3 and RFX2 gene with male infertility with azoospermia in Chinese population

Cited by 4 publications

References 24 publications

Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

Molecular characteristics and transcriptional regulatory of spermatogenesis-related gene RFX2 in adult Banna mini-pig inbred line (BMI)

Genetic Landscape of Nonobstructive Azoospermia and New Perspectives for the Clinic

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