M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination

Abstract

Following meiotic recombination, each pair of homologous chromosomes acquires at least one crossover, which ensures accurate chromosome segregation and allows reciprocal exchange of genetic information. Recombination failure often leads to meiotic arrest, impairing fertility, but the molecular basis of recombination remains elusive. Here, we report a homozygous M1AP splicing mutation (c.1074 + 2T > C) in patients with severe oligozoospermia owing to meiotic metaphase I arrest. The mutation abolishes M1AP foci on the chromosome axes, resulting in decreased recombination intermediates and crossovers in male mouse models. M1AP interacts with the mammalian ZZS (an acronym for yeast proteins Zip2‐Zip4‐Spo16) complex components, SHOC1, TEX11, and SPO16. M1AP localizes to chromosomal axes in a SPO16‐dependent manner and colocalizes with TEX11. Ablation of M1AP does not alter SHOC1 localization but reduces the recruitment of TEX11 to recombination intermediates. M1AP shows cytoplasmic localization in fetal oocytes and is dispensable for fertility and crossover formation in female mice. Our study provides the first evidence that M1AP acts as a copartner of the ZZS complex to promote crossover formation and meiotic progression in males.

Scrutinizing the human TEX genes in the context of human male infertility

“…Second, also from well-established genes in the context of male infertility like TEX14 and M1AP, it is known that the phenotype may vary between SCO and MeiA for the former 25 or between oligo-, crypto-, and azoospermia for the latter. 26,27 In line with the expression pattern in mice showing Zfand3 (Tex27) expression peaking in post-meiotic germ cells, 23 the strong expression of ZFAND3 (TEX27) during spermato-and spermiogenesis in humans suggests an essential function in late germ cell maturation. 24 F I G U R E 5 Testicular squashes revealing testicular cell composition in WT and KD Drosophila.…”

“…First, it is likely that not all the detected variants are pathogenic and, therefore, some of these men may have an alternative cause of infertility. Second, also from well‐established genes in the context of male infertility like TEX14 and M1AP , it is known that the phenotype may vary between SCO and MeiA for the former 25 or between oligo‐, crypto‐, and azoospermia for the latter 26,27 . In line with the expression pattern in mice showing Zfand3 ( Tex27) expression peaking in post‐meiotic germ cells, 23 the strong expression of ZFAND3 ( TEX27 ) during spermato‐ and spermiogenesis in humans suggests an essential function in late germ cell maturation 24 …”

Genotype-specific differences in infertile men due to loss-of-function variants inM1APorZZSgenes

“…This was strengthened by two subfertile mouse models with predominant meiotic arrest, hinting toward the protein's role during male meiosis (Arango et al, 2013;Li et al, 2023). In addition, several human cases of male infertility have been described in which azoo-, crypto-, or extreme oligozoospermia have been associated with biallelic variants in M1AP (Wyrwoll et al, 2020;Tu et al, 2020;Li et al, 2023;Khan et al, 2023). Accordingly, M1AP has achieved a strong clinical gene-disease association based on the criteria of the Clinical Genome Resource (ClinGen) Gene Curation Working Group, and, therefore, we have proposed that this gene be included in routine diagnostics of infertile men (Wyrwoll et al, 2023a).…”

“…DSB repair in pachytene (P) results in at least one crossover per chromosome pair (= obligatory crossover principle) and highly depends on SHOC1, TEX11, and SPO16 (= ZZS complex) activity. An integration of M1AP in this process was shown in mice (Li et al, 2023). B. Co-immunoprecipitation (IP) proved the interaction of human M1AP (detected by N-terminal DYK-tag) with each of the ZZS complex proteins (detected by C-terminal HA-tag).…”

“…The ZZS gene TEX11 is a well-established X-linked gene for clinical diagnostics in male infertility (Wyrwoll et al, 2023a; Yatsenko et al, 2015); biallelic pathogenic variants in SHOC1 lead to infertility in men and women (Krausz et al, 2020; Ke et al, 2023); and one homozygous splice region variant in SPO16 has recently been associated with POI (Qi et al, 2023). While a strong association between M1AP and male infertility has been demonstrated (Wyrwoll et al, 2020; Li et al, 2023), the protein’s molecular function remains unexplored in humans.…”