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

Lookup NU author(s): Dr Brendan Houston, Francesco Kumara Mastrorosa, Professor Joris VeltmanORCiD


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© 2021 American Society of Human GeneticsAsthenoteratozoospermia 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.

Publication metadata

Author(s): Liu C, Tu C, Wang L, Wu H, Houston BJ, Mastrorosa FK, Zhang W, Shen Y, Wang J, Tian S, Meng L, Cong J, Yang S, Jiang Y, Tang S, Zeng Y, Lv M, Lin G, Li J, Saiyin H, He X, Jin L, Toure A, Ray PF, Veltman JA, Shi Q, O'Bryan MK, Cao Y, Tan Y-Q, Zhang F

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2021

Volume: 108

Issue: 2

Pages: 309-323

Print publication date: 04/02/2021

Online publication date: 19/01/2021

Acceptance date: 29/12/2020

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2021.01.002

PubMed id: 33472045


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