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

Jing Tan, Yunxia Cao, Feng Zhang, Li Jin, Hongyan Wang, Zhiguo Zhang, Jiajia Wang, Yujie Chen, Shuyan Tang, Weiyu Li, Dongdong Tang, Mingrong Lv, Wangjie Liu, Huan Wu, Chunyu Liu, Shenmin Yang, Xiaojin He

Journal: Journal of human genetics 2019;64(1):49-54

PMID: 30310178

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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.

Address: 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.; Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China.; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, 230022, Hefei, China.; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, 230022, Hefei, China.; Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, 215002, Suzhou, China.; Suzhou Municipal Hospital, 215002, Suzhou, China.; 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. [email protected].; Center for Global Health, School of Public Health, Nanjing Medical University, 211116, Nanjing, China. [email protected].; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011, Shanghai, China. [email protected].; Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China. [email protected].; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, 230022, Hefei, China. [email protected].; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, 230022, Hefei, China. [email protected].

DOI: 10.1038/s10038-018-0520-1

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MeSH Terms: Calcium-Binding Proteins, Female, Homozygote, Humans, Infertility, Male, Male, Mutation, Pedigree, Prognosis, Sperm Tail, Exome Sequencing