Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Homozygous variants in PANX1 cause human oocyte death and female infertility

European Journal of Human Genetics volume 29, pages 1396–1404 (2021)Cite this article

Subjects

Abstract

PANX1, one of the members of the pannexin family, is a highly glycosylated channel-forming protein. Recently, we identified heterozygous variants in PANX1 that follow an autosomal dominant inheritance pattern and cause female infertility characterized by oocyte death. In this study, we screened for novel PANX1 variants in patients with the phenotype of oocyte death and discovered a new type of inheritance pattern accompanying PANX1 variants. We identified two novel homozygous missense variants in PANX1 [NM_015368.4 c.712T>C (p.(Ser238Pro) and c.899G>A (p.(Arg300Gln))] associated with the oocyte death phenotype in two families. Both of the homozygous variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, and resulted in mouse oocyte death after fertilization in vitro. It is worth noting that the destructive effect of the two homozygous variants on PANX1 function was weaker than that caused by the recently reported heterozygous variants. Our findings enrich the variational spectrum of PANX1 and expand the inheritance pattern of PANX1 variants to an autosomal recessive mode. This highlights the critical role of PANX1 in human oocyte development and helps us to better understand the genetic basis of female infertility due to oocyte death.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Identification of pathogenic variants in PANX1.
Fig. 2: Effects of PANX1 pathogenic variants on glycosylation and channel properties.
Fig. 3: Mimicking the oocyte death phenotype in mouse oocytes in vitro.

Similar content being viewed by others

References

  1. Tamrakar SR, Bastakoti R. Determinants of infertility in couples. J Nepal Health Res Counc. 2019;17:85–9.

    Article  Google Scholar 

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

    Article  Google Scholar 

  3. Levran D, Farhi J, Nahum H, Glezerman M, Weissman A. Maturation arrest of human oocytes as a cause of infertility: case report. Hum Reprod. 2002;17:1604–9.

    Article  Google Scholar 

  4. Edwards RG, Bavister BD, Steptoe PC. Early stages of fertilization in vitro of human oocytes matured in vitro. Nature. 1969;221:632–5.

    Article  CAS  Google Scholar 

  5. Gardner DK, Lane M. Culture and selection of viable blastocysts: a feasible proposition for human IVF? Hum Reprod Update. 1997;3:367–82.

    Article  CAS  Google Scholar 

  6. Feng R, Sang Q, Kuang Y, Sun X, Yan Z, Zhang S, et al. Mutations in TUBB8 and human oocyte meiotic arrest. N Engl J Med. 2016;374:223–32.

    Article  CAS  Google Scholar 

  7. Chen B, Zhang Z, Sun X, Kuang Y, Mao X, Wang X, et al. Biallelic mutations in PATL2 cause female infertility characterized by oocyte maturation arrest. Am J Hum Genet. 2017;101:609–15.

    Article  CAS  Google Scholar 

  8. Alazami AM, Awad SM, Coskun S, Al-Hassan S, Hijazi H, Abdulwahab FM, et al. TLE6 mutation causes the earliest known human embryonic lethality. Genome Biol. 2015;16:240.

    Article  Google Scholar 

  9. Sang Q, Li B, Kuang Y, Wang X, Zhang Z, Chen B, et al. Homozygous mutations in WEE2 cause fertilization failure and female infertility. Am J Hum Genet. 2018;102:649–57.

    Article  CAS  Google Scholar 

  10. Xu Y, Shi Y, Fu J, Yu M, Feng R, Sang Q, et al. Mutations in PADI6 cause female infertility characterized by early embryonic arrest. Am J Hum Genet. 2016;99:744–52.

    Article  CAS  Google Scholar 

  11. Mu J, Wang W, Chen B, Wu L, Li B, Mao X, et al. Mutations in NLRP2 and NLRP5 cause female infertility characterised by early embryonic arrest. J Med Genet. 2019;56:471–80.

    Article  CAS  Google Scholar 

  12. 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.

  13. Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I, et al. The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics. 2004;83:706–16.

    Article  CAS  Google Scholar 

  14. Bao L, Locovei S, Dahl G. Pannexin membrane channels are mechanosensitive conduits for ATP. Febs Lett. 2004;572:65–8.

    Article  CAS  Google Scholar 

  15. Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. Embo J. 2006;25:5071–82.

    Article  CAS  Google Scholar 

  16. Shi G, Liu C, Yang Y, Song L, Liu X, Wang C, et al. Panx1 promotes invasion-metastasis cascade in hepatocellular carcinoma. J Cancer. 2019;10:5681–8.

    Article  CAS  Google Scholar 

  17. Chen SP, Qin T, Seidel JL, Zheng Y, Eikermann M, Ferrari MD, et al. Inhibition of the P2X7-PANX1 complex suppresses spreading depolarization and neuroinflammation. Brain. 2017;140:1643–56.

    Article  Google Scholar 

  18. Sharma AK, Charles EJ, Zhao Y, Narahari AK, Baderdinni PK, Good ME, et al. Pannexin-1 channels on endothelial cells mediate vascular inflammation during lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 2018;315:L301–12.

    Article  CAS  Google Scholar 

  19. Meens MJ, Kwak BR, Duffy HS. Role of connexins and pannexins in cardiovascular physiology. Cell Mol Life Sci. 2015;72:2779–92.

    Article  CAS  Google Scholar 

  20. Molica F, Figueroa XF, Kwak BR, Isakson BE, Gibbins JM. Connexins and pannexins in vascular function and disease. Int J Mol Sci. 2018;19:1663.

    Article  Google Scholar 

  21. Zhao HB, Zhu Y, Liang C, Chen J. Pannexin 1 deficiency can induce hearing loss. Biochem Biophys Res Commun. 2015;463:143–7.

    Article  CAS  Google Scholar 

  22. Chen J, Zhu Y, Liang C, Chen J, Zhao HB. Pannexin1 channels dominate ATP release in the cochlea ensuring endocochlear potential and auditory receptor potential generation and hearing. Sci Rep. 2015;5:10762.

    Article  CAS  Google Scholar 

  23. Bargiotas P, Krenz A, Hormuzdi SG, Ridder DA, Herb A, Barakat W, et al. Pannexins in ischemia-induced neurodegeneration. Proc Natl Acad Sci USA. 2011;108:20772–7.

    Article  CAS  Google Scholar 

  24. Seminario-Vidal L, Okada SF, Sesma JI, Kreda SM, van Heusden CA, Zhu Y, et al. Rho signaling regulates pannexin 1-mediated ATP release from airway epithelia. J Biol Chem. 2011;286:26277–86.

    Article  CAS  Google Scholar 

  25. 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;30:449–51.

    Article  CAS  Google Scholar 

  26. 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;27:373–81.

    Article  CAS  Google Scholar 

  27. 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;30:452–4.

    Article  Google Scholar 

  28. 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.

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

    Article  Google Scholar 

  30. Ruan Z, Orozco IJ, Du J, Lu W. Structures of human pannexin 1 reveal ion pathways and mechanism of gating. Nature. 2020;584:646–51.

    Article  CAS  Google Scholar 

  31. Penuela S, Bhalla R, Gong XQ, 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;120:3772–83.

    Article  CAS  Google Scholar 

  32. 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;282:31733–43.

    Article  CAS  Google Scholar 

  33. Feng R, Yan Z, Li B, Yu M, Sang Q, Tian G, et al. Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos. J Med Genet. 2016;53:662–71.

    Article  CAS  Google Scholar 

  34. Chen B, Li B, Li D, Yan Z, Mao X, Xu Y, et al. Novel mutations and structural deletions in TUBB8: expanding mutational and phenotypic spectrum of patients with arrest in oocyte maturation, fertilization or early embryonic development. Hum Reprod. 2017;32:457–64.

    Article  CAS  Google Scholar 

  35. Penuela S, Simek J, Thompson RJ. Regulation of pannexin channels by post-translational modifications. Febs Lett. 2014;588:1411–5.

    Article  CAS  Google Scholar 

  36. Miyazaki S, Shirakawa H, Nakada K, Honda Y. Essential role of the inositol 1,4,5-trisphosphate receptor/Ca2+ release channel in Ca2+ waves and Ca2+ oscillations at fertilization of mammalian eggs. Dev Biol. 1993;158:62–78.

    Article  CAS  Google Scholar 

  37. Vogt EJ, Tokuhiro K, Guo M, Dale R, Yang G, Shin SW, et al. Anchoring cortical granules in the cortex ensures trafficking to the plasma membrane for post-fertilization exocytosis. Nat Commun. 2019;10:2271.

    Article  Google Scholar 

  38. Horner VL, Wolfner MF. Transitioning from egg to embryo: triggers and mechanisms of egg activation. Dev Dyn. 2008;237:527–44.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients, their families, and the healthy volunteers for participating in this study. This work was supported by the National Key Research and Development Program of China (2018YFC1003800, 2017YFC1001500, and 2016YFC1000600), the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, and 81971382), the project supported by Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), Project of Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500), Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (18SG03), the Foundation of Shanghai Health and Family Planning Commission (20154Y0162), the Capacity Building Planning Program for Shanghai Women and Children’s Health Service, the collaborative innovation center project construction for Shanghai Women and Children’s Health.

Author information

Author notes

  1. These authors contributed equally: Weijie Wang, Ronggui Qu, Qian Dou, Fengyan Wu

Authors and Affiliations

  1. Institute of Pediatrics, Children’s Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology and Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, 200032, Shanghai, China

    Weijie Wang, Ronggui Qu, Wenjing Wang, Biaobang Chen, Jian Mu, Zhihua Zhang, Lin Zhao, Zhou Zhou, Jie Dong, Yang Zeng, Ruyi Liu, Qiaoli Li, Lei Wang & Qing Sang

  2. Reproductive Medical Center, The Second Affiliated Hospital of Zhengzhou University, 450000, Zhengzhou, China

    Qian Dou

  3. Reproductive Medical Center, Affiliated Hospital of Chifeng University, Chifeng, 024005, Inner Mongolia Autonomous Region, China

    Fengyan Wu

  4. NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, 200011, Shanghai, China

    Jing Du

  5. Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, 200031, Shanghai, China

    Shujia Zhu

  6. Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, 200030, Shanghai, China

    Lin He

  7. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 200438, Shanghai, China

    Li Jin

  8. Zhuhai Fudan Innovation Institute, 519000, Zhuhai, China

    Lei Wang & Qing Sang

  9. Shanghai Center for Women and Children’s Health, 200062, Shanghai, China

    Lei Wang

Authors
  1. Weijie Wang
    View author publications

    Search author on:PubMed Google Scholar

  2. Ronggui Qu
    View author publications

    Search author on:PubMed Google Scholar

  3. Qian Dou
    View author publications

    Search author on:PubMed Google Scholar

  4. Fengyan Wu
    View author publications

    Search author on:PubMed Google Scholar

  5. Wenjing Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Biaobang Chen
    View author publications

    Search author on:PubMed Google Scholar

  7. Jian Mu
    View author publications

    Search author on:PubMed Google Scholar

  8. Zhihua Zhang
    View author publications

    Search author on:PubMed Google Scholar

  9. Lin Zhao
    View author publications

    Search author on:PubMed Google Scholar

  10. Zhou Zhou
    View author publications

    Search author on:PubMed Google Scholar

  11. Jie Dong
    View author publications

    Search author on:PubMed Google Scholar

  12. Yang Zeng
    View author publications

    Search author on:PubMed Google Scholar

  13. Ruyi Liu
    View author publications

    Search author on:PubMed Google Scholar

  14. Jing Du
    View author publications

    Search author on:PubMed Google Scholar

  15. Shujia Zhu
    View author publications

    Search author on:PubMed Google Scholar

  16. Qiaoli Li
    View author publications

    Search author on:PubMed Google Scholar

  17. Lin He
    View author publications

    Search author on:PubMed Google Scholar

  18. Li Jin
    View author publications

    Search author on:PubMed Google Scholar

  19. Lei Wang
    View author publications

    Search author on:PubMed Google Scholar

  20. Qing Sang
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Lei Wang or Qing Sang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Our study was approved by the Ethics Committee of the Medical College of Fudan University and the Reproductive Study Ethics Committee of the hospital (No. 148).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Qu, R., Dou, Q. et al. Homozygous variants in PANX1 cause human oocyte death and female infertility. Eur J Hum Genet 29, 1396–1404 (2021). https://doi.org/10.1038/s41431-020-00807-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41431-020-00807-4

This article is cited by

Search

Advanced search

Quick links