Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility

• DOI: 10.1016/j.ajhg.2021.01.002
• Publication Date: 2021-01-19T15:30:13Z
• Authors: Chunyu Liu; Chaofeng Tu; Lingbo Wang; Huan Wu; Brendan J. Houston; Francesco K. Mast...; Wen Zhang; Ying Shen; Jiaxiong Wang; Shixiong Tian; Lanlan Meng; Jiangshan Cong; Shenmin Yang; Yiwen Jiang; Shuyan Tang; Yuyan Zeng; Mingrong Lv; Ge Lin; Jinsong Li; Hexige Saiyin; Xiaojin He; Li Jin; Aminata Touré; Pierre F. Ray; Joris A. Veltman; Qinghua Shi; Moira K. O’Bryan; Yunxia Cao; Yue-Qiu Tan; Feng Zhang
• Keywords: Male; [SDV]Life Sciences [q-bio]; Mutation, Missense; 618; Cohort Studies; 03 medical and health sciences; Genes, X-Linked; Exome Sequencing; Animals; Humans; Sperm Injections, Intracytoplasmic; Infertility, Male; Hemizygote; 0303 health sciences; Spermatozoa; Pedigree; 3. Good health; Mice, Inbred C57BL; Phenotype; Asthenozoospermia; Sperm Tail; Mutation; Sperm Motility; Female; Gene Deletion

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.