The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans

Wyrwoll, Margot J.; Gaasbeek, Channah M.; Golubickaitė, Ieva; Stakaitis, Rytis; Oud, Manon S; Nagirnaja, Liina; Dion, Camille; Sindi, Emad B.; Leitch, Harry G.; Jayasena, Channa N.; Sironen, Anu; Dicke, Ann-Kristin; Rotte, Nadja; Stallmeyer, Birgit; Kliesch, Sabine; Grangeiro, Carlos Henrique Paiva; Araujo, Thaís Fenz; Lasko, Paul; D’Hauwers, Kathleen; Smits, Roos M.; Ramos, Liliana; Xavier, Miguel J; Conrad, Don F.; Almstrup, Kristian; Veltman, Joris A.; Tüttelmann, Frank; Heijden, Godfried W. van der

doi:10.1016/j.ajhg.2022.09.002

Cited by 10 publications

(8 citation statements)

References 69 publications

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“…Among the genes highlighted in this study, FKBP6 23 , PIWIL2 20,41 , PNLDC1 21,22 , PLD6 21 , HENMT1 18 , MOV10L1 42 , TDRD9 18,19,21 , and TDRD12 21 were recently described in the context of piRNA pathway dysfunction and/or human male infertility and the discovery of additional variants signi cantly strengthens the gene-disease relationship. For several of these genes, we identi ed similar testicular phenotypes as previously reported: SCO in PIWIL2 41 , round spermatid arrest in PNLDC1 22 , and hypospermatogenesis in TDRD9 variant carriers 18 , respectively.…”

Section: Discussionmentioning

confidence: 67%

“…1, also including reference transcripts). The three FKBP6 variant carriers and also one of the TDRD12 variant carriers have been described previously 21,23 . Detailed analysis of the exomes from each variant carrier did not reveal any other variants with a higher probability for causing the disease.…”

Section: Genes Encoding Pirna Biogenesis Proteins Are Frequently Muta...mentioning

confidence: 99%

“…In men, biallelic variants in several piRNA-related genes have recently been reported to cause infertility due to spermatogenic failure leading to non-obstructive azoospermia (NOA) or cryptozoospermia, i.e., no or very few spermatozoa in their ejaculate [18][19][20][21] . However, only biallelic variants in PNLDC1, FKBP6, and TDRD9 have as yet been functionally linked to a reduced levels of germ cell-derived piRNAs and, thus, impaired piRNA biogenesis [21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

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Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Stallmeyer,

Bühlmann,

Stakaitis

et al. 2024

Preprint

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Piwi-interacting RNAs (piRNAs) are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4 as novel disease genes. The testicular phenotypes repeatedly differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal spermatozoa. LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. Furthermore, an abolished expression of not only the encoded proteins but also of additional piRNA factors reveals co-dependencies within the human pathway. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.

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Section: Discussionmentioning

confidence: 67%

Section: Genes Encoding Pirna Biogenesis Proteins Are Frequently Muta...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Stallmeyer,

Bühlmann,

Stakaitis

et al. 2024

Preprint

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“…FKBP6 had higher expression at female meiosis and localized to fetal germ cells (FGC) and oogonia cell clusters (Figure 3c). In the testis, FKBP6 is required for piRNA metabolism and normal pachytene progression 17 . Here, gene expression within the developing ovary was found to be particularly enriched for piRNA-related genes.…”

Section: Resultsmentioning

confidence: 99%

Mapping the anatomical and transcriptional landscape of early human fetal ovary development

McGlacken-Byrne,

del Valle,

Xenakis

et al. 2023

Preprint

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The complex genetic mechanisms underlying human ovary development can give rise to clinical phenotypes if disrupted, such as Primary Ovarian Insufficiency and Differences of Sex Development. Through a clinically-focused lens, we combine single-nuclei RNA sequencing, bulk RNA sequencing, and micro-focus computed tomography to elucidate the anatomy and transcriptional landscape of the human fetal ovary across key developmental timepoints (Carnegie Stage 22 until 20 weeks post conception). We show the marked growth and distinct morphological changes within the fetal ovary at the critical timepoint of germ cell expansion, and demonstrate that the fetal ovary becomes more transcriptomically distinct from the testis with age. We describe novel ovary developmental pathways, relating to neuroendocrine signalling, energy homeostasis, mitochondrial networks, piRNA processes, and inflammasome regulation. We define transcriptional regulators and candidate genes for meiosis within the developing ovary. Together, this work advances our fundamental understanding of human ovary development and clinical ovarian insufficiency phenotypes.

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“…6K, L, samples separated by age, not by sex genotype). Men homozygous for pathogenic variants of FKBP6 show arrested spermatogenesis at the round-spermatid stage and have abnormal piRNA biogenesis like mouse Fkbp6 mutants (Xiol et al, 2012, Wyrwoll et al, 2022). piRNAs interact with Piwi proteins, including Piwil2 in zebrafish, which aids in transposon defense (Houwing et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Direct Male Development in Chromosomally ZZ Zebrafish

Wilson,

Batzel,

Postlethwait

2023

Preprint

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The genetics of sex determination varies across taxa, sometimes even within a species. Major domesticated strains of zebrafish (Danio rerio), including AB and TU, lack a strong genetic sex determining locus, but strains more recently derived from nature, like Nadia (NA), possess a ZZ male/ZW female chromosomal sex-determination system. AB strain fish pass through a juvenile ovary stage, forming oocytes that survive in fish that become females but die in fish that become males. To understand mechanisms of gonad development in NA zebrafish, we studied histology and single cell transcriptomics in developing ZZ and ZW fish. ZW fish developed oocytes by 22 days post-fertilization (dpf) but ZZ fish directly formed testes, avoiding a juvenile ovary phase. Gonads of some ZW and WW fish, however, developed oocytes that died as the gonad became a testis, mimicking AB fish, suggesting that the gynogenetically derived AB strain is chromosomally WW. Single-cell RNA-seq of 19dpf gonads showed similar cell types in ZZ and ZW fish, including germ cells, precursors of gonadal support cells, steroidogenic cells, interstitial/stromal cells, and immune cells, consistent with a bipotential juvenile gonad. In contrast, scRNA-seq of 30dpf gonads revealed that cells in ZZ gonads had transcriptomes characteristic of testicular Sertoli, Leydig, and germ cells while ZW gonads had granulosa cells, theca cells, and developing oocytes. Hematopoietic and vascular cells were similar in both sex genotypes. These results show that juvenile NA zebrafish initially develop a bipotential gonad; that a factor on the NA W chromosome or fewer than two Z chromosomes is essential to initiate oocyte development; and without the W factor or with two Z doses, NA gonads develop directly into testes without passing through the juvenile ovary stage. Sex determination in AB and TU strains mimics NA ZW and WW zebrafish, suggesting loss of the Z chromosome during domestication. Genetic analysis of the NA strain will facilitate our understanding of the evolution of sex determination mechanisms.

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The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans

Cited by 10 publications

References 69 publications

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Mapping the anatomical and transcriptional landscape of early human fetal ovary development

Direct Male Development in Chromosomally ZZ Zebrafish

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