Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes
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.
Authors
- Hans-Christian Schuppe (ORCID: https://orcid.org/0000-0002-0874-0439)
- Adrian Pilatz (ORCID: https://orcid.org/0000-0001-8072-1841)
- Frank Tüttelmann (ORCID: https://orcid.org/0000-0003-2745-9965)
- Verena Nordhoff (ORCID: https://orcid.org/0000-0001-5963-1366)
- Kristian Almstrup (ORCID: https://orcid.org/0000-0002-1832-0307)
- Daniela Fietz (ORCID: https://orcid.org/0000-0002-7945-1810)
- Corinna Friedrich (ORCID: https://orcid.org/0000-0001-8848-3366)
- Moira K. O’Bryan (ORCID: https://orcid.org/0000-0001-7298-4940)
- Jessica E. M. Dunleavy (ORCID: https://orcid.org/0000-0003-2009-0165)
- Sara Di Persio (ORCID: https://orcid.org/0000-0002-9279-7373)
- Ann‐Kristin Dicke (ORCID: https://orcid.org/0000-0002-2171-0525)
- Nadja Rotte (ORCID: https://orcid.org/0000-0003-0075-8842)
- Birgit Stallmeyer (ORCID: https://orcid.org/0000-0002-8590-6498)
- Sabine Kliesch (ORCID: https://orcid.org/0000-0002-7561-4870)
- Christian Rückert (ORCID: https://orcid.org/0000-0002-9722-4435)
- Nina Neuhaus (ORCID: https://orcid.org/0000-0003-0181-6194)
- Johanna Kuß
- Sofia Boeg Winge (ORCID: https://orcid.org/0000-0003-1666-1228)
- Michelle D. Runkel
- Lina Bosse
Institutions
- University of Copenhagen (DK)
- The University of Melbourne (AU)
- University of Münster (DE)
- Copenhagen University Hospital (DK)
- University Hospital Münster (DE)
- Department of Embryology (US)
- Institute of Human Genetics (PL)
- Institute of Reproductive Medicine (IN)
- Polyclinic General Hospital (GR)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1038/s44321-025-00244-0
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft
- Westfälische Wilhelms-Universität Münster