Mutations of MSH5 in nonobstructive azoospermia (NOA) and rescued via in vivo gene editing.
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ABSTRACT:
SUBMITTER: Chen M
PROVIDER: S-EPMC8724278 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Mutations of MSH5 in nonobstructive azoospermia (NOA) and rescued via in vivo gene editing.
Chen Min M Yao Chencheng C Qin Yingying Y Cui Xiuhong X Li Peng P Ji Zhiyong Z Lin Limei L Wu Haowei H Zhou Zhi Z Gui Yaoting Y Li Zheng Z Gao Fei F
Signal transduction and targeted therapy 20220103 1
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Project description: Not available
| S-EPMC10521963 | biostudies-literature
Project description:The genetic background of the non-obstructive azoospermia (NOA) remains poorly known. However, recent studies employing next generation sequencing techniques were able to uncover some NOA causative genes, among which was the TKTL1 gene. In this article we aim to understand the function of the TKTL1 gene in human spermatogenesis by inducing its overexpression in human testicular primary cells (hTPc), which we verified in male gonad tissue samples collected from NOA patients by uncovering the genes cluster regulated by TKTL1. Successful overexpression of the TKTL1 gene was achieved in hTP cells, the TKTL1 gene expression level was significantly higher in modified cells compared to both control groups (p<0.01). Using RNA-seq, we selected 20 genes which expression levels significantly differed in the modified hTP cells overexpressing TKTL1 gene in comparison to both controls. Male gonad tissue samples collected from NOA patients harbouring a mutation in the TKTL1 gene showed a significant downregulation (p<0.05) in HERC5, CSF3, HES1 and HSPA1B genes, compared to both controls, which was in accordance with the results obtained for hTPc cells, as the overexpression of the TKTL1 gene correlated with an increased expression level of the named genes compared to control groups.
2025-05-01 | GSE262557 | GEO
Project description:Nonobstructive azoospermia (NOA) is a severe form of male infertility. The molecular basis of NOA is still poorly understood. The aim of this study was to explore the associations between single nucleotide polymorphisms (SNPs) of the TATA-box binding protein associated factor 4b (TAF4B) gene and NOA. A total of 100 Han Chinese patients with NOA and 100 healthy men as controls were recruited. Targeted gene capture sequencing was performed. A total of 11 TAF4B SNPs were screened in the NOA and control subjects. Six synonymous and 4 nonsynonymous variants were detected. The c.11G>T (p.G4V) mutation was detected only in NOA patients. Polymorphism Phenotyping v2 and Sorting Intolerant From Tolerant analysis indicated that the p.G4V mutation influenced the protein structure of TAF4B. Haplotype analysis showed that the candidate SNPs did not independently associate with NOA and were found at extremely low frequencies in the subject population. Mutation Taster analysis indicated that the c.11G>T/p.G4V mutation was damaging. WebLogo analysis showed that the residue at amino acid 4 was relatively conserved. The p.Gly4Val substitution may affect the structure of the TAF4B protein. The c.11G>T mutation of the TAF4B gene may be associated with NOA in a Chinese population. Bioinformatics analysis indicated this variation may play an important role in the process of spermatogenesis.
| S-EPMC7306362 | biostudies-literature
Project description:Nonobstructive azoospermia (NOA) refers to the failure of spermatogenesis, which affects approximately 1% of the male population and contributes to 10% of male infertility. NOA has an underlying basis of endocrine imbalances since proper human spermatogenesis relies on complex regulation and cooperation of multiple hormones. A better understanding of subtle hormonal disturbances in NOA would help design and improve hormone therapies with reduced risk in human fertility clinics. The purpose of this review is to summarize the research on the endocrinological aspects of NOA, especially the hormones involved in hypothalamic-pituitary-testis axis (HPTA), including gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, estradiol, sex hormone binding globulin, inhibin B, anti-Müllerian hormone, and leptin. For the NOA men associated with primary testicular failure, the quality of currently available evidence has not been sufficient enough to recommend any general hormone optimization therapy. Some other NOA patients, especially those with hypogonadotropic hypogonadism, could be treated with hormonal replacement. Although these approaches have succeeded in resuming the fertility in many NOA patients, the prudent strategies should be applied in individuals according to specific NOA etiology by balancing fertility benefits and potential risks. This review also discusses how NOA can be induced by immunization against hormones.
| S-EPMC9226686 | biostudies-literature
Project description:ObjectiveThe aim of this study was to evaluate whether ubiquitin-specific peptidase 26 (USP26) gene variations were associated with nonobstructive azoospermia (NOA).MethodsSeven hundred and seventy-six patients diagnosed with NOA and 709 proven fertile men were included in this study. Genetic variations of infertility-related genes, including USP26, were identified by selected exonic sequencing. The effects of USP26 mutations on androgen receptor (AR) binding, ubiquitination, and transcriptional activity were detected by immunoprecipitation and luciferase assay in Hela and TM4 cells.ResultsSix novel missense mutations and 1 novel synonymous mutation of USP26 unique to the patients with NOA were identified. Of these missense mutations, USP26 R344W remarkably reduced the binding affinity and deubiquitinating activity of USP26 to AR, thus eliminated the inhibitory effect of USP26 on transcriptional activity of AR in Hela and TM4 cells.ConclusionA novel USP26 variant p.R344W is associated with NOA probably through affecting AR function.
| S-EPMC5933177 | biostudies-literature
Project description:BackgroundThe molecular mechanism of nonobstructive azoospermia (NOA) remains unclear. The aim of this study was to identify gene expression changes in NOA patients and to explore potential biomarkers and therapeutic targets.MethodsThe gene expression profiles of GSE45885 and GSE145467 were collected from the Gene Expression Omnibus (GEO) database, and the differences between NOA and normal spermatogenesis were analyzed. Enrichment analysis was performed to explore biological functions for common differentially expressed genes (DEGs) in GSE45885 and GSE145467. Coexpression analysis of DEGs in GSE45885 was performed, and two modules with the highest correlation with NOA were screened. Key genes were then screened from the intersection genes of the two modules and common DEGs and PPI network. The expression of key genes was validated by quantitative real-time polymerase chain reaction (qRT-PCR) experiments. Finally, through miRTarBase, miRDB, and RAID, the miRNAs were predicted to regulate key genes, respectively.ResultsA total of 345 common DEGs were identified and they were mainly related to spermatogenesis, insulin signaling pathway. Coexpression analysis of DEGs in GSE45885 yielded eight modules; MEblack and MEturquoise had the highest correlation with NOA. Six genes in MEturquoise and RNF141 in MEblack were identified as key genes. qRT-PCR experiments validated the differential expression of key genes between NOA and control. Furthermore, RNF141 was regulated by the largest number of miRNAs.ConclusionOur findings suggest that the significant change expression of key genes may be potential markers and therapeutic targets of NOA and may have some impact on the development of NOA.
| S-EPMC8211532 | biostudies-literature
Project description:PurposeIt is estimated that 40-50% of infertility among human couples is due to male infertility. Azoospermia is estimated to occur in 1% of all men and to be the cause of 10-20% of male infertility. Genetic defects, including single gene effects, maybe cause of azoospermia in 20-30% of affected males. Here, we aim to identify the genetic cause of azoospermia in a man who is also affected by hereditary spastic paraplegia.MethodsThe proband was subjected to whole-exome sequencing, followed by a comprehensive in silico analysis to identify the azoospermia causative gene.ResultsA novel splice site mutation c.375-2A > G in SYCE1 that is thought to be the cause of azoospermia was identified. This variant co-segregated with azoospermia status in the family that has three additional affected males.ConclusionSYCE1 gene encodes synaptonemal complex (SC) central element 1 protein which contributes to the formation of the synaptonemal complex during meiosis. Syce1 null male and female mice have been shown to be infertile. There have only been two reports on the effects of SYCE1 mutations in humans; it was shown as the cause of primary ovarian failure (POI) in one and as the cause of nonobstructive azoospermia (NOA) in another. We suggest that the mutation 375-2A > G, which affects the acceptor splice site within intron 6 of SYCE1, is the likely cause of azoospermia and subsequent infertility in the family studied. The finding constitutes the third report of SYCE1mutations that affect infertility in humans and further supports its contribution to this condition.
| S-EPMC7056785 | biostudies-literature
Project description:Infertility is a problem that affects approximately 15% of couples, and male infertility is responsible for 40-50% of these cases. The cause of male infertility is still poorly diagnosed and treated. One of the prominent causes of male infertility is disturbed spermatogenesis, which can lead to nonobstructive azoospermia (NOA). Whole-genome sequencing (WGS) allows us to identify novel rare variants in potentially NOA-associated genes, among others, in the ESX1 gene. The aim of this study was to activate the ESX1 gene using CRISPRa technology in human germ cells (testicular seminoma cells-TCam-2). Successful activation of the ESX1 gene in TCam-2 cells using the CRISPRa system was achieved, and the expression level of the ESX1 gene was significantly higher in modified TCam-2 cells than in WT cells or the negative control with nontargeted gRNA (p < 0.01). Using RNA-seq, a network of over 50 genes potentially regulated by the ESX1 gene was determined. Finally, 6 genes, NANOG, CXCR4, RPS6KA5, CCND1, PDE1C, and LINC00662, participating in cell proliferation and differentiation were verified in azoospermic patients with and without a mutation in the ESX1 gene as well as in men with normal spermatogenesis, where inverse correlations in the expression levels of the observed genes were noted.
| S-EPMC10545701 | biostudies-literature
Project description:The clinical management of men with nonobstructive azoospermia (NOA) seeking fertility has been a challenge for andrologists, urologists, and reproductive medicine specialists alike. This review presents a personal perspective on the clinical management of NOA, including the lessons learned over 15 years dealing with this male infertility condition. A five-consecutive-step algorithm is proposed to manage such patients. First, a differential diagnosis of azoospermia is made to confirm/establish that NOA is due to spermatogenic failure. Second, genetic testing is carried out not only to detect the males in whom NOA is caused by microdeletions of the long arm of the Y chromosome, but also to counsel the affected patients about their chances of having success in sperm retrieval. Third, it is determined whether any intervention prior to a surgical retrieval attempt may be used to increase sperm production. Fourth, the most effective and efficient retrieval method is selected to search for testicular sperm. Lastly, state-of-art laboratory techniques are applied in the handling of retrieved gametes and cultivating the embryos resulting from sperm injections. A coordinated multidisciplinary effort is key to offer the best possible chance of achieving a biological offspring to males with NOA.
| S-EPMC4430952 | biostudies-other
Project description:PurposeMale infertility is a multifactorial syndrome encompassing a wide variety of disorders. A previous Chinese genome-wide single-nucleotide polymorphism (SNP) association studies have identified four SNPs (rs12097821 in PRMT6 gene, rs2477686 in PEX10 gene, rs6080550 in SIRPA-SIRPG, and rs10842262 in SOX5 gene) as being significantly associated with risk factors for nonobstructive azoospermia (NOA). However, the results were not fully repeated in later studies, which calls for further investigations.MethodsWe here performed a case-control study in a central Chinese population to explore the association between the four SNPs and male infertility, which included 631 infertile men (NOA and oligozoospermia) and 720 healthy fertile men. The genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism and confirmed by sequencing.ResultsThe results showed that rs12097821 and rs10842262 were strongly associated with the risk of NOA but not total male infertility or oligozoospermia, while rs2477686 and rs6080550 were not associated with the risk of total male infertility, NOA, or oligozoospermia. To improve the statistical strength, a meta-analysis was conducted. The results suggested that rs2477686, rs6080550, and rs10842262 were significantly associated with male infertility, especially with NOA, while rs12097821 was only found to be associated with total male infertility.ConclusionsCollectively, the rs2477686, rs6080550, and rs10842262 may indeed be the genetic risk factors for NOA, which requires further investigation using larger independent sets of samples in different ethnic populations.
| S-EPMC6505017 | biostudies-literature