Unravelling the human piRNA pathway in spermatogenic failure: Genetic, functional, and mechanistic insights

• Applicant: Dr. Birgit Stallmeyer
• Subject Area: Reproductive Medicine, Urology ; General Genetics and Functional Genome Biology ; Human Genetics
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 581622950

Non-obstructive azoospermia (NOA), defined by the absence of sperm in the ejaculate due to spermatogenic failure, represents the most severe form of male infertility. While established genetic causes, such as Klinefelter syndrome and Y-chromosomal AZF deletions, account for approximately 20% of cases, monogenic causes remain largely underdiagnosed, highlighting a major diagnostic gap in reproductive medicine. piRNAs represent a subgroup of small non-coding regulatory RNAs which plays a central role in maintaining germline integrity, primarily through the silencing of transposable elements. Recent findings demonstrate that biallelic high-impact variants in piRNA pathway genes are enriched among patients with spermatogenic failure and male infertility. Although piRNA biogenesis and function are overall evolutionarily conserved, emerging data, including differences in the phenotype caused by variants in distinct genes and in the pattern of transposon activation compared to murine models, point towards the existence of human-specific mechanisms. This project will take a multi-pronged approach, combining (1) interactome mapping of key human piRNA factors, (2) functional characterisation of novel piRNA pathway factors, and biallelic variants in candidate genes (3) and deciphering of novel high-impact variants in piRNA pathway genes. By integrating genetic, proteomic, and functional data, this project will enhance our understanding of piRNA-mediated gene regulation in human spermatogenesis. The anticipated outcomes will provide novel insights into species-specific RNA-based regulatory mechanisms in the human germline and contribute to improved molecular and clinical diagnostics of male infertility.

• DFG Programme: Research Grants