Male infertility and meiotic arrest have been linked to M1AP, the gene encoding meiosis I associated protein. In mice, M1AP interacts with the ZZS proteins SHOC1, TEX11, and SPO16, which promote DNA crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by disrupting crossover formation, we screened for biallelic or hemizygous loss-of-function (LoF) variants in the encoding human genes to select men with a presumed protein deficiency; we compiled N=10 men for M1AP, N=4 for SHOC1, N=9 for TEX11, and the first homozygous LoF variant in SPO16 in an infertile man. After in-depth characterisation of the testicular phenotype of these men, we identified gene-specific meiotic impairments: Men with SHOC1, TEX11, or SPO16 deficiency shared an early meiotic arrest lacking haploid germ cells. All men with LoF variants in M1AP exhibited a predominant metaphase I arrest with rare haploid round spermatids, and six men even produced sporadic elongated spermatids. These differences were explained by different recombination failures: abrogated SHOC1, TEX11, or SPO16 led to incorrect synapsis of homologous chromosomes and unrepaired DNA double-strand breaks (DSB). On the contrary, abolished M1AP did not affect synapsis and DSB repair but led to a reduced number of crossover events. Notably, 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 not essential, catalyser in the network of ZZS-mediated meiotic recombination.

The authors have declared no competing interest.

This study was carried out within the frame of the German Research Foundation-funded Clinical Research Unit Male Germ Cells (DFG CRU326, project number 329621271) to CF, FT, NN and the German Academic Exchange Service (DAAD) to FT and MOB (project ID 57511796).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All individuals gave written informed consent compliant with local requirements. The MERGE study was approved by the Ethics Committee of the Aerztekammer Westfalen-Lippe and the Medical Faculty Muenster: Muenster #2010-578-f-S, #2012-555-f-S; Giessen #26/11), study of GEMINI-377 was approved by the ethics committee for the Capital Region in Denmark #H-2-2014-103, all in accordance with the Helsinki Declaration of 1975.

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Sequencing data of the MERGE study is available by contacting the Institute of Reproductive Genetics (https://reprogenetik.de). Access to this data is limited for each case and specific consent of the respective samples. All novel variants have been submitted to ClinVar (SCV004708228 - SCV004708242).

https://reprogenetik.de

https://www.ncbi.nlm.nih.gov/clinvar/