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Am J Hum Genet. 2017 Jun 1;100(6):854-864. doi: 10.1016/j.ajhg.2017.04.012. Epub 2017 May 25.

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella.

Author information

1
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China; Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
2
Department of Surgery, Medical College of Shandong University, Jinan 250012, China; Reproductive Medicine Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, China.
3
Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
4
Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China; Department of ART, Institute of Urology, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
5
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China.
6
Genesky Biotechnologies Inc., Shanghai 200120, China.
7
Center for Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou 215002, China.
8
Jinghua Hospital, Shenyang Eastern Medical Group, Shenyang 110005, China.
9
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China; Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200032, China.
10
Research Center for Medical Genomics, Ministry of Education Key Laboratory of Medical Cell Biology, College of Basic Medical Science, China Medical University, Shenyang 110122, China.
11
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
12
Center for Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou 215002, China. Electronic address: drim2004@126.com.
13
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China; Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China. Electronic address: zhangfeng@fudan.edu.cn.

Abstract

Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAF-associated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia- and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43- and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

KEYWORDS:

CFAP43; CFAP44; CFAP65; CGH; cilia; flagella; male infertility; motility; sequencing; sperm

PMID:
28552195
PMCID:
PMC5473723
DOI:
10.1016/j.ajhg.2017.04.012
[Indexed for MEDLINE]
Free PMC Article

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