Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella

doi:10.1136/jmedgenet-2018-105486

. 2019 Feb;56(2):96-103.

doi: 10.1136/jmedgenet-2018-105486. Epub 2018 Nov 10.

Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella

Xiaojin He^#^{1

2

3}, Weiyu Li^#^{4

5

6}, Huan Wu^#^{1

2

3}, Mingrong Lv^{1

2

3}, Wangjie Liu^{4

6}, Chunyu Liu^{4

6}, Fuxi Zhu^{1

2

3}, Caihua Li⁷, Youyan Fang^{1

2}, Chenyu Yang⁸, Huiru Cheng², Junqiang Zhang², Jing Tan^{1

2

3}, Tingting Chen⁹, Dongdong Tang^{1

2

3}, Bing Song^{1

2

3}, Xue Wang^{1

2

3}, Xiaomin Zha^{1

2

3}, Hongyan Wang^{4

6}, Zhaolian Wei^{1

2

3}, Shenmin Yang¹⁰, Hexige Saiyin⁴, Ping Zhou^{1

2

3}, Li Jin⁴, Jian Wang¹¹, Zhiguo Zhang^{1

2

3}, Feng Zhang^{4

5

6}, Yunxia Cao^{1

2

3}

Affiliations

¹ Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
² Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China.
³ Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China.
⁴ Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
⁵ State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
⁶ NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China.
⁷ Genesky Biotechnologies Inc, Shanghai, China.
⁸ Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, China.
⁹ Department of Pathology, Anhui Medical University, Hefei, China.
¹⁰ Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
¹¹ Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.

^# Contributed equally.

PMID: 30415212
DOI: 10.1136/jmedgenet-2018-105486

Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella

Xiaojin He et al. J Med Genet. 2019 Feb.

. 2019 Feb;56(2):96-103.

doi: 10.1136/jmedgenet-2018-105486. Epub 2018 Nov 10.

Authors

Affiliations

¹ Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
² Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China.
³ Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China.
⁴ Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
⁵ State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
⁶ NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China.
⁷ Genesky Biotechnologies Inc, Shanghai, China.
⁸ Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, China.
⁹ Department of Pathology, Anhui Medical University, Hefei, China.
¹⁰ Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
¹¹ Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.

^# Contributed equally.

PMID: 30415212
DOI: 10.1136/jmedgenet-2018-105486

Abstract

Background: Male infertility is a major issue of human reproduction health. Asthenoteratospermia can impair sperm motility and cause male infertility. Asthenoteratospermia with multiple morphological abnormalities of the flagella (MMAF) presents abnormal spermatozoa with absent, bent, coiled, short and/or irregular-calibre flagella. Previous studies on MMAF reported that genetic defects in cilia-related genes (eg, AKAP4, DNAH1, CFAP43, CFAP44 and CFAP69) are the major cause of MMAF. However, the known MMAF-associated genes are only responsible for approximately 30% to 50% of human cases. We further investigated the cases with MMAF in search of additional genes mutated in this condition.

Methods and results: We conducted whole exome sequencing in a male individual with MMAF from a consanguineous Han Chinese family. Sanger sequencing was also conducted in additional individuals with MMAF. Intriguingly, a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis. The subsequent Sanger sequencing of the CFAP69 coding regions among 34 additional individuals with MMAF revealed a case with homozygous nonsense mutation (p.Trp216*) of CFAP69. Both of these CFAP69 loss-of-function mutations were not present in the human population genome data archived in the 1000 Genomes Project and ExAC databases, nor in 875 individuals of two Han Chinese control populations. Furthermore, we generated the knockout model in mouse orthologue Cfap69 using the CRISPR-Cas9 technology. Remarkably, male Cfap69-knockout mice manifested with MMAF phenotypes.

Conclusion: Our experimental findings elucidate that homozygous loss-of-function mutations in CFAP69 can lead to asthenoteratospermia with MMAF in humans and mice.

Keywords: CFAP69; flagella; knockout mice; male infertility; sequencing.

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Conflict of interest statement

Competing interests: None declared.

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Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella

Affiliations

Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella

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