Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility
Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility
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DOI：
10.1038/s10038-018-0520-1
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发表时间：
2019-01-01
影响因子：
3.5
通讯作者：
Cao, Yunxia
中科院分区：
文献类型：
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作者：
Li, Weiyu;He, Xiaojin;Cao, Yunxia
精子鞭毛形态异常（MMAF）是由于精子鞭毛发育异常而引起的人类生殖系统疾病。MMAF患者的精子表现为无鞭毛、短鞭毛、卷曲鞭毛、弯曲鞭毛和/或不规则鞭毛。以前的研究揭示了人类MMAF的遗传贡献，但已知的MMAF相关基因只能解释大约50%的MMAF病例。在这项研究中，我们采用人类全外显子组测序进行遗传分析，并确定了CFAP 251（纤毛和鞭毛相关蛋白251，也称为WDR 66）的双等位基因突变在三个（5%）的65名汉族男性MMAF。所有这些CFAP 251突变都是功能丧失。人群基因组数据表明，这些CFAP 251突变在人群中极为罕见（仅为杂合子）或不存在。我们的基因表达和免疫荧光染色的功能测定在CFAP 251缺陷的人，连同以前的实验证据从模式生物，表明CFAP 251参与鞭毛功能。我们的观察表明CFAP 251与精子鞭毛发育和人类男性不育相关。
Multiple morphological abnormalities of flagella (MMAF) are human reproduction disorders due to the dysplastic development of sperm flagella. The spermatozoa of men with MMAF manifest absent, short, coiled, bent, and/or irregular-caliber flagella. Previous studies revealed genetic contributions to human MMAF, but known MMAF-associated genes only explained approximately 50% MMAF cases. In this study, we employed human whole-exome sequencing for genetic analysis and identified biallelic mutations of CFAP251 (cilia- and flagella-associated protein 251, also known as WDR66) in three (5%) of 65 Han Chinese men with MMAF. All these CFAP251 mutations are loss-of-function. The population genome data suggested that these CFAP251 mutations are extremely rare (only heterozygous) or absent from human populations. Our functional assays of gene expression and immunofluorescence staining in a CFAP251 -deficient man, together with previous experimental evidence from model organisms, suggested that CFAP251 is involved in flagellar functions. Our observations suggested that CFAP251 is associated with sperm flagellar development and human male infertility.