男性不育
生物
精子
卵胞浆内精子注射
不育
男科
鞭毛
生物信息学
遗传学
精子无力症
候选基因
精子发生
无精子症
表型
外显子组测序
基因
医学
内分泌学
怀孕
作者
Tongyao Hu,Lanlan Meng,Chen Tan,Chen Luo,Wen‐Bin He,Chaofeng Tu,Huan Zhang,Juan Du,Hongchuan Nie,Guangxiu Lu,Jing Guo,Yue‐Qiu Tan
标识
DOI:10.1136/jmedgenet-2021-108249
摘要
The genetic causes for most male infertility due to severe oligoasthenoteratozoospermia (OAT) remain unclear.To identify the genetic cause of male infertility characterised by OAT.Variant screening was performed by whole-exome sequencing from 325 infertile patients with OAT and 392 fertile individuals. In silico and in vitro analyses were performed to evaluate the impacts of candidate disease-causing variants. A knockout mouse model was generated to confirm the candidate disease-causing gene, and intracytoplasmic sperm injection (ICSI) was used to evaluate the efficiency of clinical treatment.We identified biallelic CFAP61 variants (NM_015585.4: c.1654C>T (p.R552C) and c.2911G>A (p.D971N), c.144-2A>G and c.1666G>A (p.G556R)) in two (0.62%) of the 325 OAT-affected men. In silico bioinformatics analysis predicted that all four variants were deleterious, and in vitro functional analysis confirmed the deleterious effects of the mutants. Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants. Further immunofluorescence assays revealed markedly reduced CFAP61 staining in the sperm flagella. In addition, Cfap61-deficient mice showed the OAT phenotype, suggesting that loss of function of CFAP61 was the cause of OAT. Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby.Our findings indicate that CFAP61 is essential for spermatogenesis and that biallelic CFAP61 variants lead to male infertility in humans and mice with OAT.
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