1. Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility
- Author
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Yiwen Jiang, Chaofeng Tu, Lingbo Wang, Hexige Saiyin, Ying Shen, Li Jin, Huan Wu, Francesco K. Mastrorosa, Jinsong Li, Aminata Touré, Ge Lin, Mingrong Lv, Brendan J Houston, Joris A. Veltman, Shuyan Tang, Feng Zhang, Yuyan Zeng, Yue-Qiu Tan, Jiangshan Cong, Jiaxiong Wang, Shixiong Tian, Yunxia Cao, Qinghua Shi, Chunyu Liu, Xiaojin He, Shenmin Yang, Moira K O'Bryan, Lanlan Meng, Pierre F. Ray, and Wen Zhang
- Subjects
Male ,0301 basic medicine ,Genetic counseling ,Population ,Mutation, Missense ,Biology ,Genome ,Article ,Male infertility ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Genes, X-Linked ,Exome Sequencing ,Genetics ,medicine ,Animals ,Humans ,Missense mutation ,Sperm Injections, Intracytoplasmic ,education ,Gene ,Infertility, Male ,Genetics (clinical) ,Hemizygote ,education.field_of_study ,030219 obstetrics & reproductive medicine ,medicine.disease ,Spermatozoa ,Phenotype ,Sperm ,Pedigree ,Mice, Inbred C57BL ,030104 developmental biology ,Asthenozoospermia ,Sperm Tail ,Mutation ,Sperm Motility ,Female ,Gene Deletion - Abstract
Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.
- Published
- 2021