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J Med Genet. 2019 Sep 9. pii: jmedgenet-2019-106344. doi: 10.1136/jmedgenet-2019-106344. [Epub ahead of print]

Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice.

Li W#1,2,3,4, Wu H#4,5,6, Li F#7,8, Tian S1,2, Kherraf ZE9,10, Zhang J11, Ni X4,5,6, Lv M4,5,6, Liu C1,2,3,4, Tan Q4,5,6, Shen Y12, Amiri-Yekta A9,10,13, Cazin C9,10, Zhang J4,5,6, Liu W1,2,3, Zheng Y7,8, Cheng H4,5,6, Wu Y7,8, Wang J4,5,6, Gao Y4,5,6, Chen Y4,5,6, Zha X4,5,6, Jin L1, Liu M11, He X4,5,6, Ray PF9,10, Cao Y14,5,6, Zhang F15,2,3,4.

Author information

1
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China.
2
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
3
State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
4
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
5
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China.
6
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China.
7
Human Sperm Bank, West China Second University Hospital, Sichuan University, Chengdu, China.
8
Key Laboratory of Birth Defects and Related Disease of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
9
Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
10
Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble, France.
11
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
12
Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
13
Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, Tehran, Iran.
14
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China zhangfeng@fudan.edu.cn caoyunxia6@126.com.
15
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China zhangfeng@fudan.edu.cn caoyunxia6@126.com.
#
Contributed equally

Abstract

BACKGROUND:

Male infertility is a prevalent issue worldwide, mostly due to the impaired sperm motility. Multiple morphological abnormalities of the sperm flagella (MMAF) present aberrant spermatozoa with absent, short, coiled, bent and irregular-calibre flagella resulting in severely decreased motility. Previous studies reported several MMAF-associated genes accounting for approximately half of MMAF cases.

METHODS AND RESULT:

We conducted genetic analysis using whole-exome sequencing in 88 Han Chinese MMAF probands. CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF. All these CFAP65 mutations were null, including four frameshift mutations (c.1775delC [p.Pro592Leufs*8], c.3072_3079dup [p.Arg1027Profs*41], c.1946delC [p.Pro649Argfs*5] and c.1580delT [p.Leu527Argfs*31]) and three stop-gain mutations (c.4855C>T [p.Arg1619*], c.5270T>A [p.Leu1757*] and c.5341G>T [p.Glu1781*]). Additionally, two homozygous CFAP65 variants likely affecting splicing were identified in two MMAF-affected men of Tunisian and Iranian ancestries, respectively. These biallelic variants of CFAP65 were verified by Sanger sequencing and were absent or very rare in large data sets aggregating sequence information from various human populations. CFAP65, encoding the cilia and flagella associated protein 65, is highly and preferentially expressed in the testis. Here we also generated a frameshift mutation in mouse orthologue Cfap65 using CRISPR-Cas9 technology. Remarkably, the phenotypes of Cfap65-mutated male mice were consistent with human MMAF.

CONCLUSIONS:

Our experimental observations performed on both human subjects and on Cfap65-mutated mice demonstrate that the presence of biallelic mutations in CFAP65 causes the MMAF phenotype and impairs sperm motility.

KEYWORDS:

CFAP65; exome sequencing; male infertility; mouse model; sperm flagella

Conflict of interest statement

Competing interests: None declared.

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