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ADGB variants cause asthenozoospermia and male infertility

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Abstract

Asthenozoospermia is one of the main factors leading to male infertility, but the genetic mechanisms have not been fully elucidated. Variants in the androglobin (ADGB) gene were identified in an infertile male characterized by asthenozoospermia. The variants disrupted the binding of ADGB to calmodulin. Adgb–/– male mice were infertile due to reduced sperm concentration (< 1 × 106 /mL) and motility. Spermatogenesis was also abnormal, with malformation of both elongating and elongated spermatids, and there was an approximately twofold increase in apoptotic cells in the cauda epididymis. These exacerbated the decline in sperm motility. It is surprising that ICSI with testicular spermatids allows fertilization and eventually develops into blastocyst. Through mass spectrometry, we identified 42 candidate proteins that are involved in sperm assembly, flagella formation, and sperm motility interacting with ADGB. In particular, CFAP69 and SPEF2 were confirmed to bind to ADGB. Collectively, our study suggests the potential important role of ADGB in human fertility, revealing its relevance to spermatogenesis and infertility. This expands our knowledge of the genetic causes of asthenozoospermia and provides a theoretical basis for using ADGB as an underlying genetic marker for infertile males.

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Acknowledgements

We are deeply grateful to all the patients and their families for the participation. We would like to thank Mrs. Hong Gao from the electron microscope platform of the School of Basic Medical Sciences of Fudan University and the MS platform of the Institutes of Biomedical Sciences of Fudan University.

Funding

This work was sponsored by the National Natural Science Foundation of China (82201767), the Shanghai Sailing Program (21YF1418300), and the SHIPM-pi fund No. JY201801 from Shanghai Institute of Precision Medicine, Ninth People’s Hospital Shanghai Jiao Tong University School of Medicine.

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ZY and LW collected the samples. RQ performed the experiments. BC and QL analyzed the data. RQ and QS wrote the paper. XS, YK, LW, and QS conceived and designed the experiments. JM, LZ, and WW treated the mice. ZZ, RL, and YZ constructed the plasmids and prepared the electron microscope samples. JD and QL took and processed the images. All authors approved the final manuscript.

Corresponding authors

Correspondence to Qing Sang, Biaobang Chen or Yanping Kuang.

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None of the authors declare any conflict of interest.

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All experiments were approved by the Ethics Committee of the Medical College of Fudan University and the Ninth Hospital affiliated with Shanghai Jiao Tong University. The study was performed conforming to the current Declaration of Helsinki and all individuals provided written informed consent. The animal experimental operation was approved by the ethics committee (2022JS-029).

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Qu, R., Zhang, Z., Wu, L. et al. ADGB variants cause asthenozoospermia and male infertility. Hum Genet 142, 735–748 (2023). https://doi.org/10.1007/s00439-023-02546-0

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  • DOI: https://doi.org/10.1007/s00439-023-02546-0

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