A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia
A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia
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FBXO43 纯合性功能丧失突变导致人类非梗阻性无精症
DOI：
10.1111/cge.14069
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发表时间：
2022
影响因子：
3.5
通讯作者：
Liu Mingxi
中科院分区：
文献类型：
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作者：
Wu Huan;Zhang Xin;Shen Qunshan;Liu Yiyuan;Gao Yang;Wang Guanxiong;Lv Mingrong;Hua Rong;Xu Yuping;Zhou Ping;Wei Zhaolian;Tao Fangbiao;He Xiaojin;Cao Yunxia;Liu Mingxi
非梗阻性无精子症(NOA)是由生精障碍引起的最严重的男性不育之一。尽管发现了与人类NOA相关的多个基因，但这种特发性疾病的遗传基础在很大程度上仍不清楚。FBXO43是后期促进复合体/环体(APC/C)E3连接酶的直接抑制剂，在小鼠精子发生中起着至关重要的作用。在这项研究中，我们首次通过全外显子测序在一个中国血缘关系家族的两个NOA兄弟中发现了FBXO43c.1747C >； T：p.Gln583X纯合无义突变。FBXO43在先证者的睾丸组织中缺失，在受累的生精小管中看不到FBXO43的免疫染色信号。此外，在人类中，FBXO43缺陷会导致I期早期双线期减数分裂停滞。这一结果证明了这种功能丧失突变的致病性，并证实了人类精母细胞不能在没有FBXO43的情况下完成减数分裂。在小鼠睾丸蛋白提取物中，APC/C的三个亚基，包括ANAPC2、ANAPC8和ANAPC10，被证实与FBXO43直接相互作用，而FBXO43和Skp1没有相互作用。这项研究进一步加深了我们对人类NOA基因基础的理解，并为FBXO43与男性不育提供了见解。
Non‐obstructive azoospermia (NOA) represents one of the most serious forms of male infertility caused by spermatogenic failure. Despite multiple genes found to be associated with human NOA, the genetic basis of this idiopathic disease remains largely unknown. FBXO43 is a direct inhibitor of the anaphase‐promoting complex/cyclosome (APC/C) E3 ligase and crucially important in mouse spermatogenesis. In this study, for the first time, we identified a homozygous nonsense mutation inFBXO43c.1747C > T:p.Gln583X in two NOA brothers from a Chinese consanguineous family via whole‐exome sequencing. FBXO43 was absent from testicular tissue of the proband, and FBXO43‐immunostaining signals were invisible in the affected seminiferous tubules. Furthermore, in humans, FBXO43 defects cause meiotic arrest within early diplotene of prophase I. The results here demonstrate the pathogenicity of this loss‐of‐function mutation and confirmed that spermatocytes were unable to complete meiotic divisions without FBXO43 in humans. In mouse testicular protein extracts, three subunits of the APC/C, including ANAPC2, ANAPC8 and ANAPC10, were validated to interact directly with FBXO43, whereas no interactions were detected for FBXO43 and SKP1. This study furthers our understanding of the genetic basis of human NOA and provides insights into FBXO43 and male infertility.