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 cellspecific 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.

Hypoxia‐induced apoptosis of mouse spermatocytes is mediated by HIF‐1α through a death receptor pathway and a mitochondrial pathway

“…Worldwide, approximately 10-15% of couples suffer from infertility, and male infertility contributes to more than half of these cases (Inhorn & Patrizio, 2015). Male infertility may have a variety of causes, including azoospermia, oligospermia, asthenospermia, orchitis, and varicocele (Esteves & Agarwal, 2016;Wu et al, 2016). The pathogenesis of the male diseases listed above is usually derived from two factors: a genetic factor (Liu et al, 2015;Meng et al, 2015) and an environmental factor.…”

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects onDIS3expression

“…While none of the tested candidate variants reached a significance threshold of P < 0.05 for DIS3, 6 out of 8 had P < 0.1 (P min, rs4885093 ¼ 0.071, b rs4885093 ¼ 0. 14), and all demonstrated the same direction of effect with the risk-increasing, minor allele associated with lower DIS3 expression (Table 2 and Supplementary Material, Fig. S2A).…”

“…5B). SNRPA1, a member of the splicing machinery (14), was also preferentially bound to the insertion allele probe in each experiment.…”

Small ribonucleoprotein particle protein SmD3 governs the homeostasis of germline stem cells and the crosstalk between the spliceosome and ribosome signals in Drosophila

“…U2A and its human homolog, SNRPA1, have conserved functions in male fertility in humans and flies. Germ cellspecific expression of a point mutation of human SNRPA1 (Q148R) also led to spermatogonial differentiation defects (24). Nonetheless, the U2A component does not appear to play an essential role during the earlier stages of germ cell development, nor does it have a relevant function in the formation of cyst cells.…”