Inherited Defects of piRNA Biogenesis Cause Transposon De-Repression, Impaired Spermatogenesis, and Human Male Infertility

For infertile men to receive a causal (molecular/genetic) diagnosis not only aids in coping with their situation but also helps to estimate success rates for testicular sperm extraction (TESE) and medically assisted reproduction (MAR). Having this in mind, our research group at the Institute of Reproductive Genetics, Centre of Medical Genetics, in Münster is focusing on the identification and functional characterisation of disease genes for male infertility. Of particular interest are genes in which pathogenic variants are linked to an arrest of spermatogenesis and, consequently, leading to a complete absence of sperm in the ejaculate (azoospermia). This condition is the clinically most severe form of male infertility.

The recent study provides compelling evidence that genes encoding proteins involved in the production of PIWI-interacting RNAs (piRNAs) are major contributors to human spermatogenic failure.

While the function of piRNAs has been well-characterized in mice, their role in human germ cell development is much less understood. Mouse models have shown that a disturbed production of piRNAs results in male infertility, associated with small testes and spermatogenic arrest. However, can these results be extrapolated to men?

The journey on the piRNA pathway in the human testis started with identifying a significant association between homozygous loss-of-function variants found in exome/genome data of men with significantly impaired sperm production (spermatogenic failure) and genes involved in “piRNA processing”. Accordingly, in a subsequent screening approach of genomic data from four independent cohorts of infertile men, we identified 39 men carrying high-impact biallelic variants in 14 different piRNA-related genes. These include genes of the piRNA‐induced silencing complex (piRISC) such as PIWIL1, PIWIL2, and GTSF1, genes involved in piRNA maturation such as PLD6, GPAT2, MOV10L1, and MAEL, and genes of the TDRD scaffold protein gene family.

By characterising the reproductive and testicular phenotypes of affected men, we show concordant gene-specific findings that highlight important differences between humans and mice. Our results reveal that, for several genes, the phenotype in men differs from the complete spermatogenic arrest phenotype observed in mice, indicating that findings from mouse models cannot be universally translated to all mammalians.

But what about the impact of the human piRNA pathway on transposon regulation? Our research highlights that disruption of certain piRNA biogenesis factors not only reduces piRNA levels but is also linked to the de-repression of LINE1 transposons in spermatogonia. This finding was unexpected as it is in contrast to impaired piRNA biogenesis in mice, where LINE1 de-repression was frequently observed in spermatocytes.

Returning to the men affected by infertility, this study marks a substantial advancement in the field of reproductive genetics by significantly expanding the number of candidate genes linked to male infertility and establishing a firm connection between genetically disrupted piRNA biogenesis and male infertility. The success of our journey is rooted in strong collaborations with local as well as international research groups such as the Centre of Reproductive Medicine and Andrology, Münster, Germany, the Wellcome Centre for Cell Biology, Edinburgh, UK, and Oregon National Primate Research Centre, Oregon, USA These were fostered through the International Male Infertility Genomics Consortium (IMIGC) and provided genomic data of infertile men, specific laboratory expertise and expertise on the piRNA biogenesis field. This underscores the value of assembling large patient cohorts for the study of rare diseases.

Written by: Birgit Stallmeyer, MD & Frank Tüttelmann, MD, Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster, Münster, Germany

Read the Abstract

Login