Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes
Abstract Male infertility has been linked to M1AP. In mice, M1AP interacts with the ZZS proteins SHOC1/TEX11/SPO16, promoting DNA class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by recombination failure, we screened for bi...
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Springer Nature
2025-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00244-0 |
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| author | Nadja Rotte Jessica E M Dunleavy Michelle D Runkel Lina Bosse Daniela Fietz Adrian Pilatz Johanna Kuss Ann-Kristin Dicke Sofia B Winge Sara Di Persio Christian Ruckert Verena Nordhoff Hans-Christian Schuppe Kristian Almstrup Sabine Kliesch Nina Neuhaus Birgit Stallmeyer Moira K O’Bryan Frank Tüttelmann Corinna Friedrich |
| author_facet | Nadja Rotte Jessica E M Dunleavy Michelle D Runkel Lina Bosse Daniela Fietz Adrian Pilatz Johanna Kuss Ann-Kristin Dicke Sofia B Winge Sara Di Persio Christian Ruckert Verena Nordhoff Hans-Christian Schuppe Kristian Almstrup Sabine Kliesch Nina Neuhaus Birgit Stallmeyer Moira K O’Bryan Frank Tüttelmann Corinna Friedrich |
| author_sort | Nadja Rotte |
| collection | DOAJ |
| description | Abstract Male infertility has been linked to M1AP. In mice, M1AP interacts with the ZZS proteins SHOC1/TEX11/SPO16, promoting DNA class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by recombination failure, we screened for biallelic/hemizygous loss-of-function (LoF) variants in the human genes to select men with presumed protein deficiency (N = 24). After in-depth characterisation of testicular phenotypes, we identified gene-specific meiotic impairments: men with ZZS deficiency shared an early meiotic arrest. Men with LoF variants in M1AP exhibited a predominant metaphase I arrest with rare haploid round or even elongated spermatids. These differences were explained by different recombination failures: deficient ZZS function led to incorrect synapsis of homologous chromosomes, unrepaired DNA double-strand breaks, and incomplete recombination. Abolished M1AP led to a reduced number of recombination intermediates and class I crossover. Medically assisted reproduction resulted in the birth of a healthy child, offering the possibility of fatherhood to men with LoF variants in M1AP. Our study establishes M1AP as an important, but non-essential, functional enhancer in meiotic recombination. |
| format | Article |
| id | doaj-art-0b8c2cc8d7d64646b5b1b4ca4ebb007f |
| institution | DOAJ |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-0b8c2cc8d7d64646b5b1b4ca4ebb007f2025-08-20T03:21:02ZengSpringer NatureEMBO Molecular Medicine1757-46842025-05-011761417145110.1038/s44321-025-00244-0Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genesNadja Rotte0Jessica E M Dunleavy1Michelle D Runkel2Lina Bosse3Daniela Fietz4Adrian Pilatz5Johanna Kuss6Ann-Kristin Dicke7Sofia B Winge8Sara Di Persio9Christian Ruckert10Verena Nordhoff11Hans-Christian Schuppe12Kristian Almstrup13Sabine Kliesch14Nina Neuhaus15Birgit Stallmeyer16Moira K O’Bryan17Frank Tüttelmann18Corinna Friedrich19Centre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterSchool of BioSciences and Bio21 Molecular Sciences and Biotechnology Institute, Faculty of Science, University of MelbourneCentre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterCentre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterInstitute of Veterinary Anatomy, Histology and Embryology, University of GießenClinic and Polyclinic for Urology, Paediatric Urology and Andrology, University Hospital GießenCentre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterCentre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterDepartment of Growth and Reproduction, University Hospital CopenhagenCentre of Reproductive Medicine and Andrology, University of MünsterDepartment of Medical Genetics, University Hospital MünsterCentre of Reproductive Medicine and Andrology, University of MünsterClinic and Polyclinic for Urology, Paediatric Urology and Andrology, University Hospital GießenDepartment of Growth and Reproduction, University Hospital CopenhagenCentre of Reproductive Medicine and Andrology, University of MünsterCentre of Reproductive Medicine and Andrology, University of MünsterCentre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterSchool of BioSciences and Bio21 Molecular Sciences and Biotechnology Institute, Faculty of Science, University of MelbourneCentre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterCentre of Medical Genetics, Institute of Reproductive Genetics, University of MünsterAbstract Male infertility has been linked to M1AP. In mice, M1AP interacts with the ZZS proteins SHOC1/TEX11/SPO16, promoting DNA class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by recombination failure, we screened for biallelic/hemizygous loss-of-function (LoF) variants in the human genes to select men with presumed protein deficiency (N = 24). After in-depth characterisation of testicular phenotypes, we identified gene-specific meiotic impairments: men with ZZS deficiency shared an early meiotic arrest. Men with LoF variants in M1AP exhibited a predominant metaphase I arrest with rare haploid round or even elongated spermatids. These differences were explained by different recombination failures: deficient ZZS function led to incorrect synapsis of homologous chromosomes, unrepaired DNA double-strand breaks, and incomplete recombination. Abolished M1AP led to a reduced number of recombination intermediates and class I crossover. Medically assisted reproduction resulted in the birth of a healthy child, offering the possibility of fatherhood to men with LoF variants in M1AP. Our study establishes M1AP as an important, but non-essential, functional enhancer in meiotic recombination.https://doi.org/10.1038/s44321-025-00244-0M1APMeiosisCrossoverInfertilityRecombination |
| spellingShingle | Nadja Rotte Jessica E M Dunleavy Michelle D Runkel Lina Bosse Daniela Fietz Adrian Pilatz Johanna Kuss Ann-Kristin Dicke Sofia B Winge Sara Di Persio Christian Ruckert Verena Nordhoff Hans-Christian Schuppe Kristian Almstrup Sabine Kliesch Nina Neuhaus Birgit Stallmeyer Moira K O’Bryan Frank Tüttelmann Corinna Friedrich Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes EMBO Molecular Medicine M1AP Meiosis Crossover Infertility Recombination |
| title | Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes |
| title_full | Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes |
| title_fullStr | Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes |
| title_full_unstemmed | Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes |
| title_short | Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes |
| title_sort | genotype specific differences in infertile men due to loss of function variants in m1ap or zzs genes |
| topic | M1AP Meiosis Crossover Infertility Recombination |
| url | https://doi.org/10.1038/s44321-025-00244-0 |
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