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Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans.

ABSTRACT: Processing of pre-mRNA into mRNA is an important regulatory mechanism in eukaryotes that is mediated by the spliceosome, a huge and dynamic ribonucleoprotein complex. Splicing defects are implicated in a spectrum of human disease, but the underlying mechanistic links remain largely unresolved. Using a genome-wide association approach, we have recently identified single nucleotide polymorphisms in humans that associate with nonobstructive azoospermia (NOA), a common cause of male infertility. Here, using genetic manipulation of corresponding candidate loci in Drosophila, we show that the spliceosome component SNRPA1/U2A is essential for male fertility. Loss of U2A in germ cells of the Drosophila testis does not affect germline stem cells, but does result in the accumulation of mitotic spermatogonia that fail to differentiate into spermatocytes and mature sperm. Lack of U2A causes insufficient splicing of mRNAs required for the transition of germ cells from proliferation to differentiation. We show that germ cell-specific disruption of other components of the major spliceosome manifests with the same phenotype, demonstrating that mRNA processing is required for the differentiation of spermatogonia. This requirement is conserved, and expression of human SNRPA1 fully restores spermatogenesis in U2A mutant flies. We further report that several missense mutations in human SNRPA1 that inhibit the assembly of the major spliceosome dominantly disrupt spermatogonial differentiation in Drosophila. Collectively, our findings uncover a conserved and specific requirement for the major spliceosome during the transition from spermatogonial proliferation to differentiation in the male testis, suggesting that spliceosome defects affecting the differentiation of human spermatogonia contribute to NOA.

SUBMITTER: Wu H

PROVIDER: S-EPMC4839444 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans.

Wu Hao H Sun Liwei L Wen Yang Y Liu Yujuan Y Yu Jun J Mao Feiyu F Wang Ya Y Tong Chao C Guo Xuejiang X Hu Zhibin Z Sha Jiahao J Liu Mingxi M Xia Laixin L

Proceedings of the National Academy of Sciences of the United States of America 20160328 15

Processing of pre-mRNA into mRNA is an important regulatory mechanism in eukaryotes that is mediated by the spliceosome, a huge and dynamic ribonucleoprotein complex. Splicing defects are implicated in a spectrum of human disease, but the underlying mechanistic links remain largely unresolved. Using a genome-wide association approach, we have recently identified single nucleotide polymorphisms in humans that associate with nonobstructive azoospermia (NOA), a common cause of male infertility. Her ...[more]

PMID: 27035939

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Project description:ObjectiveTo investigate the prevalence and clinical implications of biochemical hypogonadism in infertile men with nonobstructive azoospermia (NOA).DesignCohort study.SettingUniversity-affiliated tertiary center for male reproductive health.Patients767 consecutive normogonadotropic or hypergonadotropic patients with NOA undergoing infertility evaluation from 2014 to 2021.InterventionPatients aged 23-55 years underwent comprehensive clinical, hormonal, genetic, semen analysis, and histopathology evaluations and were classified on the basis of predefined baseline follicle-stimulating hormone (12 IU/L) and total testosterone (350 ng/dL) serum levels cutpoints into four groups: hypergonadotropic hypogonadal, hypergonadotropic eugonadal, normogonadotropic hypogonadal, and normogonadotropic eugonadal. All patients were naïve regarding previous sperm retrieval (SR) or hormonal therapy use.Main outcome measuresThe period prevalence of biochemical hypogonadism, defined as testosterone levels of <350 ng/dL, and the distribution of patients per group were computed. The associations between hypogonadism, clinical factors, and SR success were evaluated using multivariable logistic regression analyses. Adjusted relative risks (aRRs) and 95% confidence intervals (CIs) were estimated to assess the association between SR and patient classification.ResultsThe overall period prevalence of biochemical hypogonadism was 80.8% (95% CI 77.9%-83.4%). The prevalence of patients by group was hypergonadotropic hypogonadal (42.4%, 38.9%-45.9%), normogonadotropic hypogonadal (38.5%; 35.1%-41.9%), hypergonadotropic eugonadal (8.3%; 6.6%-10.5%), and normogonadotropic eugonadal (10.8%; 8.8%-13.2%). Reduced testicular volume and lower estradiol levels were associated with an increased likelihood of hypogonadism. Paternal age was also an independent predictor, with higher age linked to an increased likelihood of hypogonadism. Hypogonadism was less likely in patients with germ cell maturation arrest and more likely in those with Sertoli cell-only. Patients with hypergonadotropic hypogonadism had lower SR success than normogonadotropic eugonadal counterparts (aRR 0.611; 95% CI 0.398-0.855). In the subset of hypogonadal men, hypergonadotropic patients had lower SR success than normogonadotropic participants (aRR 0.632; 0.469-0.811).ConclusionThe prevalence of biochemical hypogonadism among men with NOA is substantial. Hypogonadism is associated with testicular volume, estradiol levels, age, and histopathology patterns. This condition impacts SR success and emphasizes the need for improved care for men with NOA.

Dataset Information

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans.

Publications

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans.

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