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A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens

  • Genetics
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Abstract

Purpose

Cystic fibrosis transmembrane conductance regulator (CFTR) and adhesion G protein-coupled receptor G2 (ADGRG2) have been identified as the main pathogenic genes in congenital bilateral absence of the vas deferens (CBAVD), which is an important cause of obstructive azoospermia. This study aimed to identify the disease-causing gene in two brothers with CBAVD from a Chinese consanguineous family and reveal the intracytoplasmic sperm injection (ICSI) outcomes in these patients.

Methods

Whole-exome sequencing and Sanger sequencing were used to identify the candidate pathogenic genes. Real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence were used to assess the expression of the mutant gene. Moreover, the ICSI results from both patients were retrospectively reviewed.

Results

A novel hemizygous loss-of-function mutation (c.G118T: p.Glu40*) in ADGRG2 was identified in both patients with CBAVD. This mutation is absent from the human genome databases and causes an early translational termination in the third exon of ADGRG2. Expression analyses showed that both the ADGRG2 mRNA and the corresponding protein were undetectable in the proximal epididymal tissue of ADGRG2-mutated patients. ADGRG2 expression was restricted to the apical membranes of non-ciliated epithelia in human efferent ducts, which was consistent with a previous report in mice. Both ADGRG2-mutated patients had normal spermatogenesis and had successful clinical outcomes following ICSI.

Conclusions

Our study verifies the pathogenic role of ADGRG2 in X-linked CBAVD and broadens the spectrum of ADGRG2 mutations. In addition, we found positive ICSI outcomes in the two ADGRG2-mutated CBAVD patients.

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Funding

This study was supported by the National Natural Science Foundation of China (81901541 and 81971441), Natural Science Foundation of Anhui Province (1908085QH313 and 1908085MH244), Special Foundation for Development of Science and Technology of Anhui Province (2017070802D150 and YDZX20183400004194), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310002), and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01).

Author information

Author notes

  1. Huan Wu, Yang Gao and Cong Ma contributed equally to this work.

Authors and Affiliations

  1. Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, China

    Huan Wu, Yang Gao, Cong Ma, Qunshan Shen, Jiajia Wang, Mingrong Lv, Fuxi Zhu, Nagwa Elshewy, Xiaoqing Ni, Xiaofeng Xu, Ping Zhou, Zhaolian Wei, Xiaojin He & Yunxia Cao

  2. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, China

    Huan Wu, Yang Gao, Cong Ma, Huiru Cheng, Xiaojin He & Yunxia Cao

  3. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, No 81 Meishan Road, Hefei, 230032, China

    Huan Wu, Yang Gao, Cong Ma, Huiru Cheng, Xiaojin He & Yunxia Cao

  4. Anhui Province Key Laboratory of Reproductive Health and Genetics, No 81 Meishan Road, Hefei, 230032, China

    Mingrong Lv, Huiru Cheng, Fuxi Zhu, Xiaofeng Xu, Ping Zhou & Zhaolian Wei

  5. Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, China

    Mingrong Lv, Fuxi Zhu, Xiaofeng Xu, Ping Zhou & Zhaolian Wei

  6. Obstetrics and Gynecology Hospital, School of Life Sciences, Fudan University, Shanghai, 200011, China

    Chunyu Liu, Shixiong Tian & Feng Zhang

  7. Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Qing Tan

Authors
  1. Huan Wu
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  2. Yang Gao
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  3. Cong Ma
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  4. Qunshan Shen
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  17. Feng Zhang
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  18. Xiaojin He
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  19. Yunxia Cao
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Corresponding authors

Correspondence to Xiaojin He or Yunxia Cao.

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This research was approved by the Ethical Review Board of The First Affiliated Hospital of Anhui Medical University.

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Wu, H., Gao, Y., Ma, C. et al. A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens. J Assist Reprod Genet 37, 1421–1429 (2020). https://doi.org/10.1007/s10815-020-01779-6

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