Skip to main content

Advertisement

SpringerLink
Log in

Genetic Screening of ZNF687 and PFN1 in a Paget’s Disease of Bone Cohort Indicates an Important Role for the Nuclear Localization Signal of ZNF687

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Paget’s disease of bone (PDB) is a common, late-onset bone disorder, characterized by focal increases of bone turnover that can result in bone lesions. Heterozygous pathogenic variants in the Sequestosome 1 (SQSTM1) gene are found to be the main genetic cause of PDB. More recently, PFN1 and ZNF687 have been identified as causal genes in patients with a severe, early-onset, polyostotic form of PDB, and an increased likelihood to develop giant cell tumors. In our study, we screened the coding regions of PFN1 and ZNF687 in a Belgian PDB cohort (n = 188). In the PFN1 gene, no variants could be identified, supporting the observation that variants in this gene are extremely rare in PDB. However, we identified 3 non-synonymous coding variants in ZNF687. Interestingly, two of these rare variants (p.Pro937His and p.Arg939Cys) were clustering in the nuclear localization signal of the encoded ZNF687 protein, also harboring the p.Pro937Arg variant, a previously reported disease-causing variant. In conclusion, our findings support the involvement of genetic variation in ZNF687 in the pathogenesis of classical PDB, thereby expanding its mutational spectrum.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Ralston SH (2013) Paget’s disease of bone. N Engl J Med 368(7):644–650. https://doi.org/10.1056/NEJMcp1204713

    Article  CAS  PubMed  Google Scholar 

  2. Gennari L, Rendina D et al (2019) Paget’s disease of bone. Calcif Tissue Int 104(5):483–500. https://doi.org/10.1007/s00223-019-00522-3

    Article  CAS  PubMed  Google Scholar 

  3. Michou L, Orcel P (2019) Has Paget’s bone disease become rare? Joint Bone Spine 86(5):538–541. https://doi.org/10.1016/j.jbspin.2019.01.015

    Article  PubMed  Google Scholar 

  4. Nebot Valenzuela E, Pietschmann P (2017) Epidemiology and pathology of Paget’s disease of bone—a review. Wiener Med Wochenschrt (1946) 167(1–2):2–8. https://doi.org/10.1007/s10354-016-0496-4

    Article  Google Scholar 

  5. Gennari L, Rendina D et al (2018) Paget’s disease of bone: an update on epidemiology, pathogenesis and pharmacotherapy. Expert Opin Orphan Drugs 6(8):485–496. https://doi.org/10.1080/21678707.2018.1500691

    Article  CAS  Google Scholar 

  6. Gennari L, Rendina D et al (2022) Update on the pathogenesis and genetics of Paget’s disease of bone. Front Cell Dev Biol 10:932065. https://doi.org/10.3389/fcell.2022.932065

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hocking LJ, Lucas GJ et al (2002) Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet 11(22):2735–2739. https://doi.org/10.1093/hmg/11.22.2735

    Article  CAS  PubMed  Google Scholar 

  8. Laurin N, Brown JP et al (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70(6):1582–1588. https://doi.org/10.1086/340731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Divisato G, Formicola D et al (2016) ZNF687 mutations in severe paget disease of bone associated with giant cell tumor. Am J Hum Genet 98(2):275–286. https://doi.org/10.1016/j.ajhg.2015.12.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gianfrancesco F, Rendina D et al (2013) Giant cell tumor occurring in familial Paget’s disease of bone: report of clinical characteristics and linkage analysis of a large pedigree. J Bone Miner Res 28(2):341–350. https://doi.org/10.1002/jbmr.1750

    Article  CAS  PubMed  Google Scholar 

  11. Scotto di Carlo F, Whyte MP et al (2020) The two faces of giant cell tumor of bone. Cancer Lett 489:1–8. https://doi.org/10.1016/j.canlet.2020.05.031

    Article  CAS  PubMed  Google Scholar 

  12. Scotto di Carlo F, Pazzaglia L et al (2020) ZNF687 mutations in an extended cohort of neoplastic transformations in Paget’s disease of bone: implications for clinical pathology. J Bone Miner Res 35(10):1974–1980. https://doi.org/10.1002/jbmr.3993

    Article  CAS  PubMed  Google Scholar 

  13. Divisato G, Scotto di Carlo F et al (2018) ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget’s disease of bone. Clin Genet 93(6):1240–1244. https://doi.org/10.1111/cge.13247

    Article  CAS  PubMed  Google Scholar 

  14. Merlotti D, Materozzi M et al (2020) Mutation of PFN1 gene in an early onset, polyostotic Paget-like disease. J Clin Endocrinolo Metabol. https://doi.org/10.1210/clinem/dgaa252

    Article  Google Scholar 

  15. Wei Z, Li S et al (2021) Mutations in Profilin 1 cause early-onset Paget’s disease of bone with giant cell tumors. J Bone Miner Res 36(6):1088–1103. https://doi.org/10.1002/jbmr.4275

    Article  CAS  PubMed  Google Scholar 

  16. Scotto di Carlo F, Pazzaglia L et al (2020) The loss of Profilin 1 causes early onset paget’s disease of bone. J Bone Miner Res 35(8):1387–1398. https://doi.org/10.1002/jbmr.3964

    Article  CAS  PubMed  Google Scholar 

  17. Shirakawa J, Kajikawa S et al (2019) Profilin 1 negatively regulates osteoclast migration in postnatal skeletal growth, remodeling, and homeostasis in mice. JBMR Plus 3(6):e10130

    Article  PubMed  PubMed Central  Google Scholar 

  18. Miyajima D, Hayata T et al (2012) Profilin1 regulates sternum development and endochondral bone formation. J Biol Chem 287(40):33545–33553. https://doi.org/10.1074/jbc.M111.329938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lin W, Izu Y et al (2018) Profilin1 is expressed in osteocytes and regulates cell shape and migration. J Cell Physiol 233(1):259–268. https://doi.org/10.1002/jcp.25872

    Article  CAS  PubMed  Google Scholar 

  20. Zaidi AH, Manna SK (2016) Profilin-PTEN interaction suppresses NF-κB activation via inhibition of IKK phosphorylation. Biochem J 473(7):859–872. https://doi.org/10.1042/bj20150624

    Article  CAS  PubMed  Google Scholar 

  21. Scotto di Carlo F, Russo S et al (2023) Profilin 1 deficiency drives mitotic defects and reduces genome stability. Commun Biol. 6(1):9. https://doi.org/10.1038/s42003-022-04392-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. De Ridder R, Boudin E et al (2019) Genetic variation in RIN3 in the Belgian population supports its involvement in the pathogenesis of Paget’s disease of bone and modifies the age of onset. Calcif Tissue Int 104(6):613–621. https://doi.org/10.1007/s00223-019-00530-3

    Article  CAS  PubMed  Google Scholar 

  23. De Ridder R, Vandeweyer G et al (2021) A panel-based sequencing analysis of patients with Paget’s disease of bone suggests enrichment of rare genetic variation in regulators of NF-κB signaling and supports the importance of the 7q33 locus. Calcif Tissue Int 109(6):656–665. https://doi.org/10.1007/s00223-021-00881-w

    Article  CAS  PubMed  Google Scholar 

  24. Chung PY, Beyens G et al (2010) Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget’s disease of bone. J Bone Miner Res 25(12):2592–2605. https://doi.org/10.1002/jbmr.162

    Article  CAS  PubMed  Google Scholar 

  25. Beyens G, Van Hul E et al (2004) Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget’s disease. Calcif Tissue Int 75(2):144–152. https://doi.org/10.1007/s00223-004-0244-4

    Article  CAS  PubMed  Google Scholar 

  26. Beyens G, Daroszewska A et al (2007) Identification of sex-specific associations between polymorphisms of the osteoprotegerin gene, TNFRSF11B, and Paget’s disease of bone. J Bone Miner Res 22(7):1062–1071. https://doi.org/10.1359/jbmr.070333

    Article  CAS  PubMed  Google Scholar 

  27. Fijalkowski I, Geets E et al (2016) A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone. J Bone Miner Res 31(4):874–881. https://doi.org/10.1002/jbmr.2782

    Article  CAS  PubMed  Google Scholar 

  28. Rentzsch P, Witten D et al (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucl Acids Res 47(D1):D886–D894. https://doi.org/10.1093/nar/gky1016

    Article  CAS  PubMed  Google Scholar 

  29. Huber CD, Kim BY et al (2020) Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution. Plos Genet 16(5):e1008827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Karczewski KJ, Francioli LC et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581(7809):434–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Makaram NS, Ralston SH (2021) Genetic determinants of Paget’s disease of bone. Curr Osteoporos Rep 19(3):327–337. https://doi.org/10.1007/s11914-021-00676-w

    Article  PubMed  PubMed Central  Google Scholar 

  32. Novack DV (2011) Role of NF-κB in the skeleton. Cell Res 21(1):169–182. https://doi.org/10.1038/cr.2010.159

    Article  CAS  PubMed  Google Scholar 

  33. Russo S, ScottodiCarlo F et al (2023) A mutation in the ZNF687 gene that is responsible for the severe form of Paget’s disease of bone causes severely altered bone remodeling and promotes hepatocellular carcinoma onset in a knock-in mouse model. Bone Res 11(1):16. https://doi.org/10.1038/s41413-023-00250-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Varela D, Varela T et al (2023) Regulation of human ZNF687, a gene associated with Paget’s disease of bone. Int J Biochem Cell Biol 154:106332. https://doi.org/10.1016/j.biocel.2022.106332

    Article  CAS  PubMed  Google Scholar 

  35. Ralston SH, Layfield R (2012) Pathogenesis of Paget disease of bone. Calcif Tissue Int 91:97–113. https://doi.org/10.1007/s00223-012-9599-0

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by a research grant of the University of Antwerp (Methusalem—OEC grant—“GENOMED”; FFB190208) and a grant of the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO doctoral grant R.D.R.: 1S07717N).

Author information

Authors and Affiliations

  1. Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, Antwerp, Belgium

    Yentl Huybrechts, Raphaël De Ridder, Ellen Steenackers & Wim Van Hul

  2. Department of Rheumatology, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Jean-Pierre Devogelaer

  3. Laboratory for Skeletal Dysplasia Research, Department of Human Genetics, KU Leuven and University Hospital Leuven, Louvain, Belgium

    Geert Mortier & Gretl Hendrickx

Authors
  1. Yentl Huybrechts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raphaël De Ridder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ellen Steenackers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Pierre Devogelaer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geert Mortier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gretl Hendrickx
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wim Van Hul
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YH, RDR, and ES performed the experimental work, JPD provided the patient cohort and clinical information. YH prepared the first draft of the paper. GM, GH, and WVH supervised the study and were responsible for reviewing the manuscript. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

Corresponding author

Correspondence to Wim Van Hul.

Ethics declarations

Conflict of interest

Yentl Huybrechts, Raphaël De Ridder, Ellen Steenackers, Jean-Pierre Devogelaer, Geert Mortier, Gretl Hendrickx and Wim Van Hul have no competing interests to declare that are relevant to the content of this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

Informed consent by all patients were obtained prior to the study.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huybrechts, Y., De Ridder, R., Steenackers, E. et al. Genetic Screening of ZNF687 and PFN1 in a Paget’s Disease of Bone Cohort Indicates an Important Role for the Nuclear Localization Signal of ZNF687. Calcif Tissue Int 113, 552–557 (2023). https://doi.org/10.1007/s00223-023-01137-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-023-01137-5

Keywords

Search

Navigation