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

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 class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by disrupting class I 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 class I 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, functional enhancer in the network of ZZS-mediated meiotic recombination.