ArticleAmerican journal of human genetics2022
The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 23 citations in OpenAlex.
- Unveiling the Mechanisms of Ozone-Induced Male Reproductive Toxicity: Insights from Testicular Proteomics and CTD Database.Environment & health (Washington, D.C.) · 2026Article
- The intricate dance of RNA-binding proteins: unveiling the mechanisms behind male infertility.Human reproduction update · 2026Review
- GASZ directly recruits MILI to the intermitochondrial cement for piRNA biogenesis and male germ cell development.Nucleic acids research · 2025Article
- Phenotypic continuum and poor intracytoplasmic sperm injection intracytoplasmic sperm injection prognosis in patients harboring HENMT1 variants.Andrology · 2025Article
- How exome sequencing improves the diagnostics and management of men with non-syndromic infertility.Andrology · 2025Review
- piENOX2 regulates ALKBH5-mediated Itga4 mExperimental & molecular medicine · 2025Article
- Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis.Biomolecules · 2025Article
- Fertility problems in men carrying chromosome 7 inversion: A retrospective, observational study.Medicine · 2025Observational
- Cracking the code: how piRNA pathway shapes spermatogenesis and combats male infertility.Frontiers in cell and developmental biology · 2025Review
- In-utero exposure to real-life environmental chemicals disrupts gene expression within the hypothalamo-pituitary-gonadal axis of prepubertal and adult rams.Environmental research · 2025Article
- The functions and mechanisms of piRNAs in mediating mammalian spermatogenesis and their applications in reproductive medicine.Cellular and molecular life sciences : CMLS · 2024Review
- Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility.Nature communications · 2024Article
- C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line.Molecular cell · 2024Article
- Direct male development in chromosomally ZZ zebrafish.Frontiers in cell and developmental biology · 2024Article
- Small RNAs, spermatogenesis, and male infertility: a decade of retrospect.Reproductive biology and endocrinology : RB&E · 2023Review
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Authors and funding
28 authors at 14 institutions in 9 countries.
Funding
Abstract
Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval.
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