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.

中文翻译：

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解读人类 M1AP 对 ZZS 介导的减数分裂重组和男性不育的影响

男性不育和减数分裂停滞与 M1AP 有关，M1AP 是编码减数分裂 I 相关蛋白的基因。在小鼠中，M1AP 与 ZZS 蛋白 SHOC1、TEX11 和 SPO16 相互作用，促进减数分裂过程中 DNA 交换的形成。为了确定 M1AP 和 ZZS 蛋白是否通过破坏交叉形成而与人类男性不育有关，我们筛选了编码人类基因中的双等位基因或半合子功能丧失 (LoF) 变异，以选择具有假定蛋白质缺陷的男性；我们编译了 N=10 名男性的 M1AP、N=4 的 SHOC1、N=9 的 TEX11，以及不育男性 SPO16 中的第一个纯合 LoF 变体。在对这些男性的睾丸表型进行深入表征后，我们发现了基因特异性减数分裂障碍：SHOC1、TEX11 或 SPO16 缺陷的男性都存在早期减数分裂停滞，缺乏单倍体生殖细胞。所有 M1AP 中具有 LoF 变异的男性都表现出主要的中期 I 停滞，具有罕见的单倍体圆形精子细胞，六名男性甚至产生了零星的细长精子细胞。这些差异可以通过不同的重组失败来解释：废除 SHOC1、TEX11 或 SPO16 会导致同源染色体联触不正确以及未修复的 DNA 双链断裂 (DSB)。相反，废除M1AP并不影响突触和DSB修复，但导致交叉事件数量减少。值得注意的是，医学辅助生殖带来了健康孩子的诞生，为携带 M1AP LoF 变异的男性提供了成为父亲的可能性。我们的研究证实 M1AP 是 ZZS 介导的减数分裂重组网络中重要但非必需的催化剂。