• PMID: 30415212
• Gene Name: CFAP69
• Condition: Asthenoteratospermia with multiple morphological abnormalities of the sperm flagella
• Association: Associated
• Mutation: p.Leu357Hisfs*11, p.Trp216*
• Population size: 35
• Population details: 1family , 34 individuals with MMAF
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

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

He X, Li W, Wu H, Lv M, Liu W, Liu C, Zhu F, Li C, Fang Y, Yang C, Cheng H, Zhang J, Tan J, Chen T, Tang D, Song B, Wang X, Zha X, Wang H, Wei Z, Yang S, Saiyin H, Zhou P, Jin L, Wang J, Zhang Z, Zhang F, Cao Y.

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. CI - © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. FAU - He, Xiaojin AU - He X AUID- ORCID: 0000-0001-5919-8478 AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Li, Weiyu AU - Li W AD - 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. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. AD - NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China. FAU - Wu, Huan AU - Wu H AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Lv, Mingrong AU - Lv M AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Liu, Wangjie AU - Liu W AD - 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. AD - NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China. FAU - Liu, Chunyu AU - Liu C AD - 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. AD - NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China. FAU - Zhu, Fuxi AU - Zhu F AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Li, Caihua AU - Li C AD - Genesky Biotechnologies Inc, Shanghai, China. FAU - Fang, Youyan AU - Fang Y AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. FAU - Yang, Chenyu AU - Yang C AD - Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, China. FAU - Cheng, Huiru AU - Cheng H AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. FAU - Zhang, Junqiang AU - Zhang J AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. FAU - Tan, Jing AU - Tan J AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Chen, Tingting AU - Chen T AD - Department of Pathology, Anhui Medical University, Hefei, China. FAU - Tang, Dongdong AU - Tang D AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Song, Bing AU - Song B AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Wang, Xue AU - Wang X AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Zha, Xiaomin AU - Zha X AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Wang, Hongyan AU - Wang H AD - 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. AD - NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China. FAU - Wei, Zhaolian AU - Wei Z AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Yang, Shenmin AU - Yang S AD - Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. FAU - Saiyin, Hexige AU - Saiyin H AD - 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. FAU - Zhou, Ping AU - Zhou P AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Jin, Li AU - Jin L AD - 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. FAU - Wang, Jian AU - Wang J AD - Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Zhang, Zhiguo AU - Zhang Z AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Zhang, Feng AU - Zhang F AD - 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. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. AD - NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China.