Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.

男性不育症影响约 7% 的男性，但其原因仍知之甚少。最严重的形式是非梗阻性无精子症（NOA），其部分原因是减数分裂停滞。到目前为止，仅报道了一些经过验证的疾病相关基因。为了解决这一问题，我们对 58 名患有不明原因减数分裂停滞的男性进行了全外显子组测序，并在 3 名不相关的男性中鉴定出M1AP中相同的纯合移码变异 c.676dup (p.Trp226LeufsTer4)，编码减数分裂 1 相关蛋白。该变体很可能导致截短的蛋白质，如体外突变体M1AP的异源表达所示。接下来，我们筛查了四大组不育男性，并确定了另外三名携带纯合 c.676dup 的个体，以及三名携带该变异和M1AP中其他可能致病变异的组合的个体。此外，纯合错义变异 c.1166C>T (p.Pro389Leu) 在来自土耳其近亲家庭的五名男性中导致不育。所有受影响男性的共同表型是 NOA，但偶尔在精液中观察到精子细胞，很少观察到少量精子。M1ap破坏的小鼠也有类似的表型。总的来说，这些研究结果表明，M1AP突变是常染色体隐性遗传性严重生精衰竭和男性不育的相对常见原因，具有很强的临床有效性。