MCM9基因缺陷会阻碍精子发生过程中DNA损伤的修复，导致人类出现 Sertoli 细胞单一综合征

MCM9 deficiency impairs DNA damage repair during spermatogenesis, leading to Sertoli cell-only syndrome in humans

MCM9基因缺陷会阻碍精子发生过程中DNA损伤的修复，导致人类出现 Sertoli 细胞单一综合征

Authors: Xuan Sha,Xin Zhang,Hao Geng,Yuqian Li,Xun Xia,Guotong Li,Rong Hua,Kuokuo Li,Yang Gao,Qunshan Shen,Rui Guo,Yuping Xu, Xiaojin He,Yunxia Cao,Mingxi Liu,Huan Wu

Journal: Cell Death Discovery

PMID: 40593474

DOI: 10.1038/s41420-025-02581-y

Abstract

Non-obstructive azoospermia (NOA) represents the most severe form of male infertility; however, its genetic etiology remains largely elusive. MCM9 is crucial for DNA damage repair in mammalian somatic cells, playing a key role in regulating both homologous recombination (HR) and mismatch repair (MMR) pathways. In mice, MCM9 deficiency leads to spermatogenic failure characterized by progressive germ cell depletion and impaired HR repair. However, the underlying mechanism remains unclear in humans. Our study identified two novel homozygous loss-of-function (LoF) mutations in MCM9 in two unrelated NOA patients presenting with Sertoli cell-only syndrome (SCOS). The absence of testicular MCM9 confirmed the pathogenicity of these LoF mutations. Furthermore, diminished HR-mediated DNA repair capacity observed in HEK293T cells, either lacking MCM9 or overexpressing mutant MCM9 plasmids, highlighted the deleterious impact of these LoF mutations on HR repair. Additionally, the confirmed interaction between human testicular MCM9 and both MSH2 and MLH1, alongside findings that human MCM9 is predominantly expressed in spermatogonial stem cells and spermatogonia, provides compelling evidence for the involvement of the MCM9-mediated MMR pathway in maintaining genomic integrity and supporting the viability and proliferation of spermatogonia in humans. Given the poor outcomes of microdissection testicular sperm extraction (micro-TESE) observed in both probands, we propose that biallelic LoF mutations in MCM9 may serve as non-invasive molecular biomarkers for predicting micro-TESE failure. These findings enhance our understanding of the genetic basis of human NOA, particularly SCOS, and provide valuable insights for genetic counseling and fertility guidance tailored to these patients.

摘要

非梗阻性无精子症(NOA）是男性不育症中最严重的形式；然而，其遗传病因仍 largely 未明。MCM9 在哺乳动物体细胞的 DNA 损伤修复中起着关键作用，在调节同源重组(HR）和错配修复(MMR）通路中发挥重要作用。在小鼠中，MCM9缺失导致精子发生失败，表现为生殖细胞逐渐耗竭和HR修复受损。然而，其在人类中的具体机制尚不明确。本研究在两名无关的NOA患者中发现了两种新型MCM9纯合子功能丧失(LoF）突变，这两名患者均表现为 Sertoli细胞仅存综合征(SCOS）。睾丸中MCM9的缺失证实了这些LoF突变的致病性。此外，在缺乏MCM9或过表达突变型MCM9质粒的HEK293T细胞中观察到的HR介导的DNA修复能力下降，突显了这些LoF突变对HR修复的有害影响。此外，人类睾丸MCM9与MSH2和MLH1的相互作用得到证实，且研究发现人类MCM9主要在精原干细胞和精原细胞中表达，这为MCM9介导的MMR通路在维持基因组完整性及支持人类精原细胞的存活和增殖中的作用提供了有力证据。鉴于两名受试者在微切片睾丸精子提取(micro-TESE）中均观察到不良结果，我们提出MCM9基因的双等位基因失活突变可能作为预测micro-TESE失败的非侵入性分子生物标志物。这些发现深化了我们对人类非遗传性无精症(NOA）特别是SCOS的遗传基础的理解，并为针对这些患者的遗传咨询和生育指导提供了宝贵见解。