Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF

J Med Genet. 2020 Jul;57(7):445-453. doi: 10.1136/jmedgenet-2019-106479.

Mingrong Lv ^# ¹ ² ³, Wangjie Liu ^# ⁴ ⁵ ⁶, Wangfei Chi ^# ⁷, Xiaoqing Ni ^# ¹ ² ³, Jiajia Wang ¹ ² ³, Huiru Cheng ¹ ⁸ ⁹, Wei-Yu Li ⁴ ⁵ ⁶, Shenmin Yang ¹⁰, Huan Wu ¹ ⁸ ⁹, Junqiang Zhang ¹ ⁸ ⁹, Yang Gao ¹ ² ³, Chunyu Liu ⁴ ⁵ ⁶, Caihua Li ¹¹, Chenyu Yang ¹², Qing Tan ¹ ⁸ ⁹, Dongdong Tang ¹ ⁸ ⁹, Jingjing Zhang ¹ ⁸ ⁹, Bing Song ¹ ⁸ ⁹, Yu-Jie Chen ¹ ⁸ ⁹, Qiang Li ¹ ⁸ ⁹, Yading Zhong ¹³, Zhihua Zhang ¹⁴, Hexige Saiyin ⁴, Li Jin ⁴, Yuping Xu ¹ ⁸ ⁹, Ping Zhou ¹ ⁸ ⁹, Zhaolian Wei ¹ ⁸ ⁹, Chuanmao Zhang ⁷, Xiaojin He ¹⁵ ² ³, Feng Zhang ¹⁶ ⁵ ⁶, Yunxia Cao ¹⁵ ² ³

Affiliations

1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
2 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China.
3 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China.
4 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.
5 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
6 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
7 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China.
8 Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China.
9 Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China.
10 Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
11 Genesky Biotechnologies Inc, Shanghai, Shanghai, China.
12 Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, China.
13 Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
14 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.
15 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China [email protected] [email protected] [email protected].
16 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 [email protected] [email protected] [email protected].
# Contributed equally.

PMID: 32051257 DOI: 10.1136/jmedgenet-2019-106479

Abstract

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.

Keywords

DZIP1; asthenoteratospermia; centrosome; flagella.

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