Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes

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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Main Authors: 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
Format: Article
Language:English
Published: Springer Nature 2025-05-01
Series:EMBO Molecular Medicine
Subjects:
M1AP
Meiosis
Crossover
Infertility
Recombination
Online Access:https://doi.org/10.1038/s44321-025-00244-0
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Summary: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.
ISSN:1757-4684

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