The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei 230001, China.
The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science and Technology of China, Hefei 230027, China.
Int J Mol Sci. 2022 Jun 10;23(12):6522. doi: 10.3390/ijms23126522.
Non-obstructive azoospermia (NOA), characterized by spermatogenesis failure and the absence of sperm in ejaculation, is the most severe form of male infertility. However, the etiology and pathology between meiosis-associated monogenic alterations and human NOA remain largely unknown. A homozygous mutation (c.1126del) was identified from two idiopathic NOA patients in the consanguineous family. This mutation led to the degradation of mRNA and abolished chromosome axial localization of MutSγ in spermatocytes from the affected males. Chromosomal spreading analysis of the patient's meiotic prophase I revealed that the meiosis progression was arrested at a zygotene-like stage with extensive failure of homologous synapsis and DSB repair. Therefore, our study demonstrates that the c.1126del could cause meiotic recombination failure and lead to human infertility, improving the genetic diagnosis of NOA clinically. Furthermore, the study of human spermatocytes elucidates the meiosis defects caused by variant, and reveals a conserved and indispensable role of MutSγ in human synapsis and meiotic recombination, which have not previously been well-described.
非阻塞性无精子症（NOA）的特征是精子发生失败和精液中没有精子，是男性不育症最严重的形式。然而，减数分裂相关单基因突变与人类 NOA 之间的病因和病理学仍知之甚少。从同一家族的两名特发性 NOA 患者中鉴定出纯合突变（c.1126del）。该突变导致 mRNA 的降解，并使 MutSγ 在受影响男性的精母细胞中丧失染色体轴向定位。患者减数分裂前期 I 的染色体展开分析表明，减数分裂进展停滞在类似于合线期的阶段，同源联会和 DSB 修复广泛失败。因此，我们的研究表明，c.1126del 可能导致减数分裂重组失败，导致人类不育，从而改善 NOA 的临床遗传诊断。此外，对人类精母细胞的研究阐明了由该变异引起的减数分裂缺陷，并揭示了 MutSγ 在人类联会和减数分裂重组中的保守且不可或缺的作用，这在以前尚未得到很好的描述。
