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J Hum Genet. 2018 Oct 11. doi: 10.1038/s10038-018-0520-1. [Epub ahead of print]

Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility.

Li W1, He X2,3,4, Yang S5,6, Liu C1, Wu H2,3,4, Liu W1, Lv M2,3,4, Tang D2,3,4, Tan J2,3,4, Tang S1, Chen Y2,3,4, Wang J2,3,4, Zhang Z2,3,4, Wang H1, Jin L1, Zhang F7,8,9, Cao Y10,11,12.

Author information

1
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, 200011, Shanghai, China.
2
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China.
3
Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, 230022, Hefei, China.
4
Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, 230022, Hefei, China.
5
Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, 215002, Suzhou, China.
6
Suzhou Municipal Hospital, 215002, Suzhou, China.
7
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, 200011, Shanghai, China. zhangfeng@fudan.edu.cn.
8
Center for Global Health, School of Public Health, Nanjing Medical University, 211116, Nanjing, China. zhangfeng@fudan.edu.cn.
9
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011, Shanghai, China. zhangfeng@fudan.edu.cn.
10
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China. caoyunxia6@126.com.
11
Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, 230022, Hefei, China. caoyunxia6@126.com.
12
Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, 230022, Hefei, China. caoyunxia6@126.com.

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.

PMID:
30310178
DOI:
10.1038/s10038-018-0520-1

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