Whole-exome sequencing identifies ADGB as a novel causative gene for male infertility in humans: from motility to fertilization
Yang Gao
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorLiting Liu
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorShixiong Tian
Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
Search for more papers by this authorChunyu Liu
Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
Search for more papers by this authorMingrong Lv
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorHuan Wu
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorDongdong Tang
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorBing Song
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorQunshan Shen
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China
Anhui Provincial Engineering Research Center of Biopreservation and Artificial Organs, Hefei, Anhui, China
Anhui Provincial Human Sperm Bank, The First Affiliated Hospital of Anhui Medical University, Hefei, China
Search for more papers by this authorYuping Xu
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorPing Zhou
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorZhaolian Wei
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorCorresponding Author
Feng Zhang
Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
Correspondence
Xiaojin He, Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Shanghai 200080, China.
Email: [email protected]
Yunxia Cao, Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Email: [email protected]
Feng Zhang, Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yunxia Cao
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Anhui Provincial Institute of Translational Medicine, Hefei, Anhui, China
Correspondence
Xiaojin He, Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Shanghai 200080, China.
Email: [email protected]
Yunxia Cao, Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Email: [email protected]
Feng Zhang, Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaojin He
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Correspondence
Xiaojin He, Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Shanghai 200080, China.
Email: [email protected]
Yunxia Cao, Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Email: [email protected]
Feng Zhang, Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China.
Email: [email protected]
Search for more papers by this authorYang Gao
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorLiting Liu
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorShixiong Tian
Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
Search for more papers by this authorChunyu Liu
Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
Search for more papers by this authorMingrong Lv
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorHuan Wu
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorDongdong Tang
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorBing Song
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorQunshan Shen
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China
Anhui Provincial Engineering Research Center of Biopreservation and Artificial Organs, Hefei, Anhui, China
Anhui Provincial Human Sperm Bank, The First Affiliated Hospital of Anhui Medical University, Hefei, China
Search for more papers by this authorYuping Xu
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorPing Zhou
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorZhaolian Wei
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Search for more papers by this authorCorresponding Author
Feng Zhang
Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
Correspondence
Xiaojin He, Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Shanghai 200080, China.
Email: [email protected]
Yunxia Cao, Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Email: [email protected]
Feng Zhang, Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yunxia Cao
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China
Anhui Provincial Institute of Translational Medicine, Hefei, Anhui, China
Correspondence
Xiaojin He, Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Shanghai 200080, China.
Email: [email protected]
Yunxia Cao, Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Email: [email protected]
Feng Zhang, Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaojin He
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China
Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Correspondence
Xiaojin He, Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Shanghai 200080, China.
Email: [email protected]
Yunxia Cao, Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Email: [email protected]
Feng Zhang, Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China.
Email: [email protected]
Search for more papers by this authorYang Gao, Liting Liu, and Shixiong Tian contributed equally to this work.
Abstract
Objectives
In male mice, adgb-knockout has been reported to cause male infertility with spermatogenesis defects involving flagella and acrosome. However, this remains unclear for humans.
Materials and methods
Sequencing studies were conducted in a research hospital on samples from three unrelated infertile men with severe asthenoteratozoospermia from Han Chinese families. Data were collected through rigorous in silico analysis. Sanger sequencing were performed to identify pathogenic mutations. Sperm cells from patients were characterized using electron microscopy and used to verify the pathogenicity of the genetic factors through functional assays. Intracytoplasmic sperm injections (ICSI) assays were performed in ADGB-affected males.
Main results
Herein, in a cohort of 105 Han Chinese men with idiopathic asthenoteratozoospermia, we reported the identification of bi-allelic deleterious variants of ADGB in three infertile men from unrelated families using whole-exome sequencing. We found one homozygous frameshift ADGB variant (NM_024694.4: c.2801_2802del:p.K934Rfs*33), one homozygous missense ADGB variant (NM_024694.4: c.C3167T:p.T1056I), and one compound heterozygous ADGB variant (NM_024694.4: c.C3167T:p.T1056I; c.C3197T:p.A1066V). These variants were rare in general population and were predicted to be damaging by multiple bioinformatics tools. Further, the spermatozoa from patients harboring ADGB variants showed multiple acrosome and flagellum malformations under light and electron microscopy. Functional assays revealed the structural defects associated with dysregulation of ADGB and multiple spermatogenesis proteins. Notably, the fertilization success via ICSI treatment in all three patients, as well as the normal expression of PLCζ but CaM deficiency in the spermatozoa, suggesting that ICSI other than in vitro fertilization (IVF) is an optimal treatment for ADGB-deficient patients.
Discussion and conclusion
Our findings provide new information for the molecular diagnosis of asthenoteratozoospermia and valuable reference for personalized genetic counselling and clinical treatment for these patients. The underlying risk of IVF failure behind sperm defects was highlighted.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
All data relevant to the study are included in the paper or uploaded as supporting information.
Supporting Information
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