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Heterozygous TP63 pathogenic variants in isolated primary ovarian insufficiency

  • Genetics
  • Published:
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Abstract

Purpose

Our study aimed to identify the genetic causes of non-syndromic primary ovarian insufficiency (POI) in female patients.

Methods

We performed whole exome sequencing in females suffering from isolated POI and in their available family members. Copy number variations were validated by long-range PCR and Sanger sequencing, and conservation analysis was used to evaluate the impact of sequence variants on protein composition.

Results

We detected two pathogenic TP63 heterozygous deleterious single nucleotide variants and a novel TP63 intragenic copy number alteration in three unrelated women with isolated POI. Two of these genetic variants are predicted to result in loss of transactivation inhibition of p63, whereas the third one affects the first exon of the ΔNp63 isoforms.

Conclusion

Our results broaden the spectrum of TP63-related disorders, which now includes sporadic and familial, isolated, and syndromic POI. Genomic variants that impair the transactivation inhibitory domain of the TAp63α isoform are the cause of non-syndromic POI. Additionally, variants affecting only the ΔNp63 isoforms may result in isolated POI. In patients with isolated POI, careful evaluation of genomic variants in pleiotropic genes such as TP63 will be essential to establish a full clinical spectrum and atypical presentation of a disorder.

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Data availability

Some or all datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.

References

  1. Yatsenko SA, Rajkovic A. Genetics of human female infertility. Biol Reprod. 2019;101(3):549–66.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Titus S, et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5(172):172ra21.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ruth KS, et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021;596(7872):393–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Osterburg C, Osterburg S, Zhou H, Missero C, Dötsch V. Isoform-specific roles of mutant p63 in human diseases. Cancers. 2021;13(3)3):536. https://doi.org/10.3390/cancers13030536.

  5. Osterburg C, Dotsch V. Structural diversity of p63 and p73 isoforms. Cell Death Differ. 2022;29(5):921–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Deutsch GB, et al. DNA damage in oocytes induces a switch of the quality control factor TAp63alpha from dimer to tetramer. Cell. 2011;144(4):566–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Coutandin D, Osterburg C, Srivastav RK, Sumyk M, Kehrloesser S, Gebel J, Tuppi M, Hannewald J, Schäfer B, Salah E, Mathea S, Müller-Kuller U, Doutch J, Grez M, Knapp S, Dötsch V. Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level. Elife. 2016;5:e13909. https://doi.org/10.7554/eLife.13909.

  8. Senoo M, et al. p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell. 2007;129(3):523–36.

    Article  CAS  PubMed  Google Scholar 

  9. Yang A, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999;398(6729):714–8.

    Article  CAS  PubMed  Google Scholar 

  10. Suh EK, et al. p63 protects the female germ line during meiotic arrest. Nature. 2006;444(7119):624–8.

    Article  CAS  PubMed  Google Scholar 

  11. Tuppi M, et al. Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63. Nat Struct Mol Biol. 2018;25(3):261–9.

    Article  CAS  PubMed  Google Scholar 

  12. Gonfloni S, et al. Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat Med. 2009;15(10):1179–85.

    Article  CAS  PubMed  Google Scholar 

  13. Bolcun-Filas E, et al. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science. 2014;343(6170):533–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lena AM, et al. The p63 C-terminus is essential for murine oocyte integrity. Nat Commun. 2021;12(1):383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sutton VR, van Bokhoven H. TP63-related disorders. 2010 Jun 8 [updated 2021 Apr 1]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. University of Washington, Seattle; 1993–2023.

  16. Amiel J, et al. TP63 gene mutation in ADULT syndrome. Eur J Hum Genet. 2001;9(8):642–5.

    Article  CAS  PubMed  Google Scholar 

  17. Holder-Espinasse M, et al. A new mutation in TP63 is associated with age-related pathology. Eur J Hum Genet. 2007;15(11):1115–20.

    Article  CAS  PubMed  Google Scholar 

  18. Guazzarotti L, et al. Limb-mammary syndrome (LMS) associated with internal female genitalia dysgenesia: a new genotype/phenotype correlation? Am J Med Genet A. 2008;146A(15):2001–4.

    Article  CAS  PubMed  Google Scholar 

  19. Mathorne SW, et al. Novel phenotype of syndromic premature ovarian insufficiency associated with TP63 molecular defect. Clin Genet. 2020;97(5):779–84.

    Article  CAS  PubMed  Google Scholar 

  20. Bestetti I, et al. High-resolution array-CGH analysis on 46,XX patients affected by early onset primary ovarian insufficiency discloses new genes involved in ovarian function. Hum Reprod. 2019;34(3):574–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tucker EJ, et al. TP63-truncating variants cause isolated premature ovarian insufficiency. Hum Mutat. 2019;40(7):886–92.

    CAS  PubMed  Google Scholar 

  22. Tucker EJ, et al. Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency. Hum Mutat. 2022;43(10):1443–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yatsenko SA, et al. Pathogenic variants in ZSWIM7 cause primary ovarian insufficiency. J Clin Endocrinol Metab. 2022;107(6):e2359–64.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.

    Article  PubMed  PubMed Central  Google Scholar 

  25. McWilliam H, et al. Analysis tool web services from the EMBL-EBI. Nucleic Acids Res. 2013;41(Web Server issue):W597–600.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Russo C, et al. Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome. Proc Natl Acad Sci U S A. 2018;115(5):E906–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Helton ES, Zhu J, Chen X. The unique NH2-terminally deleted (DeltaN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the DeltaN variant of p63. J Biol Chem. 2006;281(5):2533–42.

    Article  CAS  PubMed  Google Scholar 

  28. Craig AL, et al. DeltaNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation. Mol Cancer. 2010;9:195.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chan WM, et al. How many mutant p53 molecules are needed to inactivate a tetramer? Mol Cell Biol. 2004;24(8):3536–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Westfall MD, et al. The Delta Np63 alpha phosphoprotein binds the p21 and 14-3-3 sigma promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations. Mol Cell Biol. 2003;23(7):2264–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang A, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998;2(3):305–16.

    Article  CAS  PubMed  Google Scholar 

  32. Onn L, Portillo M, Ilic S, Cleitman G, Stein D, Kaluski S, Shirat I, Slobodnik Z, Einav M, Erdel F, Akabayov B, Toiber D. SIRT6 is a DNA double-strand break sensor. Elife. 2020:9:e51636. https://doi.org/10.7554/eLife.51636.

  33. van Bokhoven H, et al. p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet. 2001;69(3):481–92.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ianakiev P, et al. Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet. 2000;67(1):59–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Khandelwal KD, et al. Deletions and loss-of-function variants in TP63 associated with orofacial clefting. Eur J Hum Genet. 2019;27(7):1101–12.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wenger T, et al. Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins. Am J Med Genet A. 2018;176(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  37. Marcet-Ortega M, et al. p53 and TAp63 participate in the recombination-dependent pachytene arrest in mouse spermatocytes. PLoS Genet. 2017;13(6):e1006845.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gebel J, et al. DNA damaged induced cell death in oocytes. Molecules. 2020;25(23). https://doi.org/10.3390/molecules25235714

  39. Luan Y, et al. TAp63 determines the fate of oocytes against DNA damage. Sci Adv. 2022;8(51):eade1846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to the patients and their families for participating in this study as well as Jessica Settino for a technical assistance.

Funding

This work was supported by the National Institute of Child Health and Human Development (R01HD070647 and R21HD074278, to AR) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5T32HD007263-38 to MR-E).

Author information

Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

    Rachel K Vanderschelden & Svetlana A. Yatsenko

  2. Department of Pathology, University of California San Francisco, San Francisco, CA, USA

    Marta Rodriguez-Escriba & Aleksandar Rajkovic

  3. Division of Pediatric and Adolescent Gynecology, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

    Serena H. Chan

  4. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Andrea J. Berman

  5. Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA

    Aleksandar Rajkovic

  6. Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA

    Aleksandar Rajkovic

  7. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Serena H. Chan & Svetlana A. Yatsenko

  8. Magee-Womens Research Institute, Pittsburgh, PA, USA

    Svetlana A. Yatsenko

Authors
  1. Rachel K Vanderschelden
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  6. Svetlana A. Yatsenko
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Contributions

SHC, SAY, and AR collected the clinical information; SAY and AR conceived the experiments; RKV, MRE, SAY, and AR analyzed experimental data; MRE and AJB performed conservation analysis and in silico modeling. The manuscript was written by RKV, MRE, and SAY; reviewed by AJB, SHC, and AR. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Aleksandar Rajkovic or Svetlana A. Yatsenko.

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The authors declare no competing interests.

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Vanderschelden, R.K., Rodriguez-Escriba, M., Chan, S.H. et al. Heterozygous TP63 pathogenic variants in isolated primary ovarian insufficiency. J Assist Reprod Genet 40, 2211–2218 (2023). https://doi.org/10.1007/s10815-023-02886-w

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  • DOI: https://doi.org/10.1007/s10815-023-02886-w

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