Whole-exome sequencing identifies ADGB as a novel causative gene for male infertility in humans: from motility to fertilization

Yang Gao; Liting Liu; Shixiong Tian; Chunyu Liu; Mingrong Lv; Huan Wu; Dongdong Tang; Bing Song; Qunshan Shen; Yuping Xu; Ping Zhou; Zhaolian Wei; Feng Zhang; Yunxia Cao; Xiaojin He

doi:10.1111/andr.13605

Whole-exome sequencing identifies ADGB as a novel causative gene for male infertility in humans: from motility to fertilization

Andrology. 2024 Feb 22. doi: 10.1111/andr.13605. Online ahead of print.

Authors

Yang Gao^{1

2

3}, Liting Liu^{1

2

3}, Shixiong Tian^{4

5}, Chunyu Liu^{4

5}, Mingrong Lv^{1

2

3}, Huan Wu^{1

2

3}, Dongdong Tang^{1

2

3}, Bing Song^{1

2

3}, Qunshan Shen^{1

6

7

8}, Yuping Xu^{1

2

3}, Ping Zhou^{1

2

3}, Zhaolian Wei^{1

2

3}, Feng Zhang^{4

5}, Yunxia Cao^{1

2

3

9}, Xiaojin He^{2

10}

Affiliations

¹ Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
² NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China.
³ Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China.
⁴ Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
⁵ Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China.
⁶ Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China.
⁷ Anhui Provincial Engineering Research Center of Biopreservation and Artificial Organs, Hefei, Anhui, China.
⁸ Anhui Provincial Human Sperm Bank, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁹ Anhui Provincial Institute of Translational Medicine, Hefei, Anhui, China.
¹⁰ Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

PMID: 38385883
DOI: 10.1111/andr.13605

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.

Keywords: ADGB; acrosome; asthenoteratozoospermia; flagella; male infertility.

Abstract

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