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A novel heterozygous variant in PANX1 causes primary infertility due to oocyte death

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Variants in the pannexin1 (PANX1) gene have been reported to be associated with oocyte death and recurrent in vitro fertilization failure. In this study, we performed genetic analysis in the patient with female infertility due to oocyte death to identify the disease-causing gene variant in the patient.

Methods

We characterized one patient from a non-consanguineous family who had suffered from oocyte death and female infertility. Whole-exome sequencing and Sanger sequencing were used to identify the variant in the family. Western blot analysis was used to check the effect of the variant on PANX1 glycosylation pattern in vitro.

Results

We identified a novel heterozygous PANX1 variant (NM_015368.4 c.976_978del, (p.Asn326del)) associated with the phenotype of oocyte death in a non-consanguineous family, followed by an autosomal dominant (AD) mode. This variant showed a more delayed emergence of oocyte death than previously reported articles. Western blot analysis confirmed that the deletion variant of PANX1 (c.976_978del) altered the glycosylation pattern in HeLa cells.

Conclusions

Our findings expand the variant spectrum of PANX1 genes associated with oocyte death and provide new support for the genetic diagnosis of female infertility.

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Data Availability

All data generated and analyzed in this study are included in this published manuscript.

References

  1. Fei C-F, Zhou L-Q. Gene mutations impede oocyte maturation, fertilization, and early embryonic development. BioEssays. 2022;44(10):e2200007.

    Article  Google Scholar 

  2. DeAngelis AM, Martini AE, Owen CM. Assisted reproductive technology and epigenetics. Semin Reprod Med. 2018;36(3–04):221–32.

    Article  Google Scholar 

  3. Sang Q, Zhou Z, Mu J, Wang L. Genetic factors as potential molecular markers of human oocyte and embryo quality. J Assist Reprod Genet. 2021;38(5).

  4. Whyte-Fagundes P, Zoidl G. Mechanisms of pannexin1 channel gating and regulation. Biochim Biophys Acta Biomembr. 2018;1860(1):65–71.

    Article  CAS  Google Scholar 

  5. Jin Q, Zhang B, Zheng X, Li N, Xu L, Xie Y, et al. Cryo-EM structures of human pannexin 1 channel. Cell Res. 2020;30(5):449–51.

    Article  CAS  Google Scholar 

  6. Qu R, Dong L, Zhang J, Yu X, Wang L, Zhu S. Cryo-EM structure of human heptameric Pannexin 1 channel. Cell Res. 2020;30(5):446–8.

    Article  Google Scholar 

  7. Deng Z, He Z, Maksaev G, Bitter RM, Rau M, Fitzpatrick JAJ, et al. Cryo-EM structures of the ATP release channel pannexin 1. Nat Struct Mol Biol. 2020;27(4):373–81.

    Article  CAS  Google Scholar 

  8. Michalski K, Syrjanen JL, Henze E, Kumpf J, Furukawa H, Kawate T. The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition. Elife. 2020;9.

  9. Penuela S, Bhalla R, Gong X-Q, Cowan KN, Celetti SJ, Cowan BJ, et al. Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins. J Cell Sci. 2007;120(Pt 21):3772–83.

    Article  CAS  Google Scholar 

  10. Boassa D, Ambrosi C, Qiu F, Dahl G, Gaietta G, Sosinsky G. Pannexin1 channels contain a glycosylation site that targets the hexamer to the plasma membrane. J Biol Chem. 2007;282(43):31733–43.

    Article  CAS  Google Scholar 

  11. Billaud M, Chiu Y-H, Lohman AW, Parpaite T, Butcher JT, Mutchler SM, et al. A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells. Sci Signal. 2015;8(364):ra17.

    Article  CAS  Google Scholar 

  12. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, et al. Pannexin 1 channels mediate “find-me” signal release and membrane permeability during apoptosis. Nature. 2010;467(7317):863–7.

    Article  CAS  Google Scholar 

  13. Di Virgilio F, Sarti AC, Falzoni S, De Marchi E, Adinolfi E. Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer. 2018;18(10):601–18.

    Article  Google Scholar 

  14. Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature. 2014;509(7500):310–7.

    Article  CAS  Google Scholar 

  15. Sang Q, Zhang Z, Shi J, Sun X, Li B, Yan Z, et al. A pannexin 1 channelopathy causes human oocyte death. Sci Transl Med. 2019;11(485).

  16. Wang W, Qu R, Dou Q, Wu F, Wang W, Chen B, et al. Homozygous variants in PANX1 cause human oocyte death and female infertility. Eur J Hum Genet. 2021;29(9):1396–404.

    Article  CAS  Google Scholar 

  17. Wu X-W, Liu P-P, Zou Y, Xu D-F, Zhang Z-Q, Cao L-Y, et al. A novel heterozygous variant in PANX1 is associated with oocyte death and female infertility. J Assist Reprod Genet. 2022;39(8):1901–8.

    Article  Google Scholar 

  18. Zhou X, Zhu L, Hou M, Wu Y, Li Z, Wang J, et al. Novel compound heterozygous mutations in WEE2 causes female infertility and fertilization failure. J Assist Reprod Genet. 2019;36(9):1957–62.

    Article  Google Scholar 

  19. Liu Z, Xi Q, Zhu L, Yang X, Jin L, Wang J, et al. TUBB8 mutations cause female infertility with large polar body oocyte and fertilization failure. Reprod Sci. 2021;28(10):2942–50.

    Article  CAS  Google Scholar 

  20. Nielsen BS, Toft-Bertelsen TL, Lolansen SD, Anderson CL, Nielsen MS, Thompson RJ, et al. Pannexin 1 activation and inhibition is permeant-selective. J Physiol. 2020;598(2):361–79.

    Article  CAS  Google Scholar 

  21. Narahari AK, Kreutzberger AJ, Gaete PS, Chiu Y-H, Leonhardt SA, Medina CB, et al. ATP and large signaling metabolites flux through caspase-activated pannexin 1 channels. Elife. 2021;10.

  22. Yang K, Xiao Z, He X, Weng R, Zhao X, Sun T. Mechanisms of pannexin 1 (PANX1) channel mechanosensitivity and its pathological roles. Int J Mol Sci. 2022;23(3).

  23. Laird DW, Penuela S. Pannexin biology and emerging linkages to cancer. Trends Cancer. 2021;7(12):1119–31.

    Article  CAS  Google Scholar 

  24. Kuzuya M, Hirano H, Hayashida K, Watanabe M, Kobayashi K, Terada T, et al. Structures of human pannexin-1 in nanodiscs reveal gating mediated by dynamic movement of the N terminus and phospholipids. Sci Signal. 2022;15(720):eabg6941.

    Article  CAS  Google Scholar 

  25. Mou L, Ke M, Song M, Shan Y, Xiao Q, Liu Q, et al. Structural basis for gating mechanism of Pannexin 1 channel. Cell Res. 2020;30(5):452–4.

    Article  Google Scholar 

  26. Bhat EA, Sajjad N. Human pannexin 1 channel: insight in structure-function mechanism and its potential physiological roles. Mol Cell Biochem. 2021;476(3):1529–40.

    Article  CAS  Google Scholar 

  27. Penuela S, Simek J, Thompson RJ. Regulation of pannexin channels by post-translational modifications. FEBS Lett. 2014;588(8):1411–5.

    Article  CAS  Google Scholar 

  28. Qian J, Nguyen NMP, Rezaei M, Huang B, Tao Y, Zhang X, et al. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. Eur J Hum Genet. 2018;26(7):1007–13.

    Article  CAS  Google Scholar 

  29. Cao Q, Zhao C, Zhang X, Zhang H, Lu Q, Wang C, et al. Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human. J Cell Mol Med. 2020;24(15):8557–66.

    Article  CAS  Google Scholar 

  30. Chu K, He Y, Wang L, Ji Y, Hao M, Pang W, et al. Novel ZP1 pathogenic variants identified in an infertile patient and a successful live birth following ICSI treatment. Clin Genet. 2020;97(5):787–8.

    Article  CAS  Google Scholar 

  31. Wang F, Yuan R-Y, Li L, Meng T-G, Fan L-H, Jing Y, et al. Mitochondrial regulation of [Ca]i oscillations during cell cycle resumption of the second meiosis of oocyte. Cell Cycle. 2018;17(12):1471–86.

    Article  CAS  Google Scholar 

  32. Rojas J, Hinostroza F, Vergara S, Pinto-Borguero I, Aguilera F, Fuentes R, et al. Knockin’ on egg’s door: maternal control of egg activation that influences cortical granule exocytosis in animal species. Front Cell Dev Biol. 2021;9:704867.

    Article  Google Scholar 

  33. Pan B, Li J. The art of oocyte meiotic arrest regulation. Reprod Biol Endocrinol. 2019;17(1):8.

    Article  Google Scholar 

  34. Georgadaki K, Khoury N, Spandidos DA, Zoumpourlis V. The molecular basis of fertilization (Review). Int J Mol Med. 2016;38(4):979–86.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Qing Sang and Lei Wang from Fudan University for providing the gift of PANX1 antibody. We also thank the patient and her family for their participation and support in this study.

Funding

This work was supported by the research grants from the National Key Research & Development Program of China (2021YFC2700603) and Health Commission of Hubei Province scientific research project (WJ2021M110).

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Author notes

  1. Zhou Li, Lixia Zhu, and Lei Jin contribute equally to the research.

Authors and Affiliations

  1. Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan, 430030, China

    Juepu Zhou, Meng Wang, Juan Hu, Zhou Li, Lixia Zhu & Lei Jin

Authors
  1. Juepu Zhou
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  2. Meng Wang
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  3. Juan Hu
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  4. Zhou Li
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  5. Lixia Zhu
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  6. Lei Jin
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Contributions

Juepu Zhou: Literature review, writing and revising of text and tables. Meng Wang: Lead for prediction model, literature review, writing and revising. Juan Hu: Tables, figures, literature review. Zhou Li: Literature review and revising. Lixia Zhu: Conception and design, writing and revising. Lei Jin: Primary supervisor, conception and design, writing and revising.

Corresponding authors

Correspondence to Zhou Li, Lixia Zhu or Lei Jin.

Ethics declarations

Ethics approval and consent to participate

This study has been approved by the Ethics Committee of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. Reference number for ethics approval is TJ-IRB20220450. Written informed consent was obtained from the participants.

Conflict of interest

The authors declare no competing interests.

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Zhou, J., Wang, M., Hu, J. et al. A novel heterozygous variant in PANX1 causes primary infertility due to oocyte death. J Assist Reprod Genet 40, 65–73 (2023). https://doi.org/10.1007/s10815-022-02666-y

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  • DOI: https://doi.org/10.1007/s10815-022-02666-y

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