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The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606565/ https://www.ncbi.nlm.nih.gov/pubmed/36150389 http://dx.doi.org/10.1016/j.ajhg.2022.09.002 |
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author | Wyrwoll, Margot J. Gaasbeek, Channah M. Golubickaite, 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 H.P. Araujo, Thaís F. Lasko, Paul D’Hauwers, Kathleen Smits, Roos M. Ramos, Liliana Xavier, Miguel J. Conrad, Don F. Almstrup, Kristian Veltman, Joris A. Tüttelmann, Frank van der Heijden, Godfried W. |
author_facet | Wyrwoll, Margot J. Gaasbeek, Channah M. Golubickaite, 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 H.P. Araujo, Thaís F. Lasko, Paul D’Hauwers, Kathleen Smits, Roos M. Ramos, Liliana Xavier, Miguel J. Conrad, Don F. Almstrup, Kristian Veltman, Joris A. Tüttelmann, Frank van der Heijden, Godfried W. |
author_sort | Wyrwoll, Margot J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9606565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-96065652023-04-06 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. Golubickaite, 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 H.P. Araujo, Thaís F. Lasko, Paul D’Hauwers, Kathleen Smits, Roos M. Ramos, Liliana Xavier, Miguel J. Conrad, Don F. Almstrup, Kristian Veltman, Joris A. Tüttelmann, Frank van der Heijden, Godfried W. Am J Hum Genet Article 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. Elsevier 2022-10-06 2022-09-22 /pmc/articles/PMC9606565/ /pubmed/36150389 http://dx.doi.org/10.1016/j.ajhg.2022.09.002 Text en Crown Copyright © 2022. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Wyrwoll, Margot J. Gaasbeek, Channah M. Golubickaite, 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 H.P. Araujo, Thaís F. Lasko, Paul D’Hauwers, Kathleen Smits, Roos M. Ramos, Liliana Xavier, Miguel J. Conrad, Don F. Almstrup, Kristian Veltman, Joris A. Tüttelmann, Frank van der Heijden, Godfried W. The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans |
title | The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans |
title_full | The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans |
title_fullStr | The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans |
title_full_unstemmed | The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans |
title_short | The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans |
title_sort | pirna-pathway factor fkbp6 is essential for spermatogenesis but dispensable for control of meiotic line-1 expression in humans |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606565/ https://www.ncbi.nlm.nih.gov/pubmed/36150389 http://dx.doi.org/10.1016/j.ajhg.2022.09.002 |
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