Tian Shixiong, Tu Chaofeng, He Xiaojin, Meng Lanlan, Wang Jiaxiong, Tang Shuyan, Gao Yang, Liu Chunyu, Wu Huan, Zhou Yiling, Lv Mingrong, Lin Ge, Jin Li, Cao Yunxia, Tang Dongdong, Zhang Feng, Tan Yue-Qiu
Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China.
J Med Genet. 2023 Aug;60(8):827-834. doi: 10.1136/jmg-2022-108887. Epub 2023 Jan 2.
Spermatogenic impairments can lead to male infertility by different pathological conditions, such as multiple morphological abnormalities of the sperm flagella (MMAF) and non-obstructive azoospermia (NOA). Genetic factors are involved in impaired spermatogenesis.
Here, we performed genetic analyses through whole-exome sequencing in a cohort of 334 Han Chinese probands with severe MMAF or NOA. Biallelic variants of were identified in three unrelated men, including one homozygous frameshift variant (c.3317del, p.Phe1106Serfs*19) and two compound heterozygous variants (c.878G>A, p.Arg293His; c.955C>T, p.Arg319Cys and c.4885C>T, p.Arg1629Cys; c.937G>A, p.Gly313Arg). All of the identified variants were absent or extremely rare in the public human genome databases and predicted to be damaging by bioinformatic tools. The men harbouring mutations exhibited abnormal sperm morphology, reduced sperm concentration and motility in ejaculated semen. Significant axoneme disorganisation and other ultrastructure abnormities were also detected inside the sperm cells from men harbouring mutations. Furthermore, immunofluorescence assays showed remarkably reduced staining of four flagellar assembly-associated proteins (IFT20, IFT52, IFT122 and SPEF2) in the spermatozoa of deficient men. Notably, favourable clinical pregnancy outcomes were achieved with sperm from men carrying mutations after intracytoplasmic sperm injection treatment.
Our genetic analyses and experimental observations revealed that biallelic deleterious mutations of can induce severe MMAF and NOA in humans.
生精障碍可通过多种病理状况导致男性不育，如精子鞭毛多重形态异常（MMAF）和非梗阻性无精子症（NOA）。遗传因素参与了生精功能受损。
在此，我们对334名患有严重MMAF或NOA的汉族先证者进行了全外显子测序的遗传分析。在三名无亲缘关系的男性中鉴定出了双等位基因变异，包括一个纯合移码变异（c.3317del，p.Phe1106Serfs*19）和两个复合杂合变异（c.878G>A，p.Arg293His；c.955C>T，p.Arg319Cys和c.4885C>T，p.Arg1629Cys；c.937G>A，p.Gly313Arg）。所有鉴定出的变异在公共人类基因组数据库中均不存在或极为罕见，并且通过生物信息学工具预测具有损害性。携带该基因变异的男性射出精液中精子形态异常、精子浓度降低且活力下降。在携带该基因变异男性的精子细胞内还检测到显著的轴丝紊乱和其他超微结构异常。此外，免疫荧光分析显示，该基因缺陷男性的精子中四种鞭毛组装相关蛋白（IFT20、IFT52、IFT122和SPEF2）的染色明显减少。值得注意的是，经胞浆内单精子注射治疗后，携带该基因变异男性的精子实现了良好的临床妊娠结局。
我们的遗传分析和实验观察表明，该基因的双等位基因有害突变可在人类中诱发严重的MMAF和NOA。
