Abstract
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.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol. 2017;18:533–47.
Lehti MS, Sironen A. Formation and function of the manchette and flagellum during spermatogenesis. Reproduction. 2016;151:R43–54.
Nowicka-Bauer K, Kurpisz M. Current knowledge of the human sperm proteome. Expert Rev Proteom. 2013;10:591–605.
Shang Y, Yan J, Tang W, Liu C, Xiao S, Guo Y, et al. Mechanistic insights into acephalic spermatozoa syndrome-associated mutations in the human SUN5 gene. J Biol Chem. 2018;293:2395–407.
Ben Khelifa M, Coutton C, Zouari R, Karaouzene T, Rendu J, Bidart M, et al. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94:95–104.
Tang S, Wang X, Li W, Yang X, Li Z, Liu W, et al. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2017;100:854–64.
Coutton C, Vargas AS, Amiri-Yekta A, Kherraf ZE, Ben Mustapha SF, Le Tanno P, et al. Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human. Nat Commun. 2018;9:686.
Dong FN, Amiri-Yekta A, Martinez G, Saut A, Tek J, Stouvenel L, et al. Absence of CFAP69 causes male infertility due to multiple morphological abnormalities of the flagella in human and mouse. Am J Hum Genet. 2018;102:636–48.
Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589–95.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
1000 Genomes Project Consortium. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–73.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Wu N, Ming X, Xiao J, Wu Z, Chen X, Shinawi M, et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med. 2015;372:341–50.
The GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60.
Smith TF. Diversity of WD-repeat proteins. Subcell Biochem. 2008;48:20–30.
Pazour GJ, Agrin N, Leszyk J, Witman GB. Proteomic analysis of a eukaryotic cilium. J Cell Biol. 2005;170:103–13.
Dymek EE, Smith EF. A conserved CaM- and radial spoke associated complex mediates regulation of flagellar dynein activity. J Cell Biol. 2007;179:515–26.
Yang P, Diener DR, Rosenbaum JL, Sale WS. Localization of calmodulin and dynein light chain LC8 in flagellar radial spokes. J Cell Biol. 2001;153:1315–26.
Smith EF, Yang P. The radial spokes and central apparatus: mechano-chemical transducers that regulate flagellar motility. Cell Motil Cytoskelet. 2004;57:8–17.
Neesen J, Kirschner R, Ochs M, Schmiedl A, Habermann B, Mueller C, et al. Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency. Hum Mol Genet. 2001;10:1117–28.
Urbanska P, Song K, Joachimiak E, Krzemien-Ojak L, Koprowski P, Hennessey T, et al. The CSC proteins FAP61 and FAP251 build the basal substructures of radial spoke 3 in cilia. Mol Biol Cell. 2015;26:1463–75.
Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–8.
Kherraf ZE, Amiri-Yekta A, Dacheux D, Karaouzene T, Coutton C, Christou-Kent M, et al. A homozygous ancestral SVA-insertion-mediated deletion in WDR66 induces multiple morphological abnormalities of the sperm flagellum and male infertility. Am J Hum Genet. 2018;103:400–12.
Auguste Y, Delague V, Desvignes JP, Longepied G, Gnisci A, Besnier P, et al. Loss of calmodulin- and radial-spoke-associated complex protein CFAP251 leads to immotile spermatozoa lacking mitochondria and infertility in men. Am J Hum Genet. 2018;103:413–20.
Acknowledgements
This work was supported by National Key Research and Development Program of China (2016YFC0905100), National Natural Science Foundation of China (31625015 and 31521003), Foundation of the Education Department of Anhui Province (KJ2016A370), Foundation of the Department of Science and Technology of Anhui Province (2017070802D150), Shanghai Medical Center of Key Programs for Female Reproductive Diseases (2017ZZ01016), and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical statement
We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Li, W., He, X., Yang, S. et al. Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility. J Hum Genet 64, 49–54 (2019). https://doi.org/10.1038/s10038-018-0520-1
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s10038-018-0520-1
This article is cited by
-
Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility
Nature Communications (2025)
-
Mouse radial spoke 3 is a metabolic and regulatory hub in cilia
Nature Structural & Molecular Biology (2025)
-
Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella
Journal of Assisted Reproduction and Genetics (2024)
-
CCDC28A deficiency causes sperm head defects, reduced sperm motility and male infertility in mice
Cellular and Molecular Life Sciences (2024)
-
Deleterious variant in FAM71D cause male infertility with asthenoteratospermia
Molecular Genetics and Genomics (2024)
