• PMID: 32051257
• Gene Name: DZIP1
• Condition: Asthenoteratospermia with severe MMAF
• Association: Associated
• Mutation: c.188G>A (p.Arg63Gln), c.690T>G (p.Tyr230*)
• Population size: 877
• Population details: 877 (875 controls, 2 cases)
• Sex: Male
• Infertility type: Male infertility

Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF

Lv M, Liu W, Chi W, Ni X, Wang J, Cheng H, Li WY, Yang S, Wu H, Zhang J, Gao Y, Liu C, Li C, Yang C, Tan Q, Tang D, Zhang J, Song B, Chen YJ, Li Q, Zhong Y, Zhang Z, Saiyin H, Jin L, Xu Y, Zhou P, Wei Z, Zhang C, He X, Zhang F, Cao Y.

BACKGROUND: Asthenoteratospermia, one of the most common causes for male infertility, often presents with defective sperm heads and/or flagella. Multiple morphological abnormalities of the sperm flagella (MMAF) is one of the common clinical manifestations of asthenoteratospermia. Variants in several genes including DNAH1, CEP135, CATSPER2 and SUN5 are involved in the genetic pathogenesis of asthenoteratospermia. However, more than half of the asthenoteratospermia cases cannot be explained by the known pathogenic genes. METHODS AND RESULTS: Two asthenoteratospermia-affected men with severe MMAF (absent flagella in >90% spermatozoa) from consanguineous families were subjected to whole-exome sequencing. The first proband had a homozygous missense mutation c.188G>A (p.Arg63Gln) of DZIP1 and the second proband had a homozygous stop-gain mutation c.690T>G (p.Tyr230*). Both of the mutations were neither detected in the human population genome data (1000 Genomes Project, Exome Aggregation Consortium) nor in our own data of a cohort of 875 Han Chinese control populations. DZIP1 encodes a DAZ (a protein deleted in azoospermia) interacting protein, which was associated with centrosomes in mammalian cells. Immunofluorescence staining of the centriolar protein Centrin1 indicated that the spermatozoa of the proband presented with abnormal centrosomes, including no concentrated centriolar dot or more than two centriolar dots. HEK293T cells transfected with two DZIP1-mutated constructs showed reduced DZIP1 level or truncated DZIP1. The Dzip1-knockout mice, generated by the CRSIPR-Cas9, revealed consistent phenotypes of severe MMAF. CONCLUSION: Our study strongly suggests that homozygous DZIP1 mutations can induce asthenoteratospermia with severe MMAF. The deficiency of DZIP1 induces sperm centrioles dysfunction and causes the absence of flagella. CI - © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 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 - NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China. AD - Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. FAU - Liu, Wangjie AU - Liu W AD - 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. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. FAU - Chi, Wangfei AU - Chi W AD - Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China. FAU - Ni, Xiaoqing AU - Ni X AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China. AD - Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. FAU - Wang, Jiajia AU - Wang J AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China. AD - Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. FAU - Cheng, Huiru AU - Cheng 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 - Li, Wei-Yu AU - Li WY AD - 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. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. FAU - Yang, Shenmin AU - Yang S AD - Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 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 - Zhang, Junqiang AU - Zhang 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 - Gao, Yang AU - Gao Y AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China. AD - Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. FAU - Liu, Chunyu AU - Liu C AD - 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. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. FAU - Li, Caihua AU - Li C AD - Genesky Biotechnologies Inc, Shanghai, Shanghai, China. FAU - Yang, Chenyu AU - Yang C AD - Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, China. FAU - Tan, Qing AU - Tan Q 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 - 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 - Zhang, Jingjing AU - Zhang 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 - Song, Bing AU - Song B AUID- ORCID: 0000-0002-7182-0175 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, Yu-Jie AU - Chen YJ 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, Qiang AU - Li Q 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 - Zhong, Yading AU - Zhong Y AD - Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. FAU - Zhang, Zhihua AU - Zhang Z AD - Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China. FAU - Saiyin, Hexige AU - Saiyin H AD - 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. FAU - Jin, Li AU - Jin L AD - 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. FAU - Xu, Yuping AU - Xu 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. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, 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 - 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 - Zhang, Chuanmao AU - Zhang C AD - Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China. 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 hxj0117@126.com zhangfeng@fudan.edu.cn caoyunxia6@126.com. AD - NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China. AD - Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. FAU - Zhang, Feng AU - Zhang F AUID- ORCID: 0000-0003-4556-8276 AD - 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 hxj0117@126.com zhangfeng@fudan.edu.cn caoyunxia6@126.com. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.