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.

  • Letter
  • Published:

Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia

Abstract

Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation1. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis2,3,4,5. Its population incidence has been estimated at 1 per million in the United Kingdom4, but it is likely to be higher in the Middle East and Gulf States6. Affected individuals are asymptomatic in early childhood2,3. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age2,3,4,5,6,7, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones5. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Clinical and radiographic findings in a 13-year-old male PPD patient.
Figure 2: Schematic depicting WISP3 protein domains and the mutations identified in PPD patients.
Figure 3: WISP3 is expressed in skeletally derived cells.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Bork, P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett. 327, 125 –130 (1993).

    Article  CAS  Google Scholar 

  2. El-Shanti, H.E., Omari, H.Z. & Qubain, H.I. Progressive pseudorheumatoid dysplasia: report of a family and review. J. Med. Genet. 34, 559–563 (1997).

    Article  CAS  Google Scholar 

  3. Rezai-Delui, H., Mamoori, G., Sadri-Mahvelatie, E. & Noori, N.M. Progressive pseudorheumatoid chondrodysplasia: a report of nine cases in three families. Skeletal Radiol. 23, 411– 419 (1994).

    Article  CAS  Google Scholar 

  4. Wynne-Davies, R., Hall, C. & Ansell, B.M. Spondylo-epiphysial dysplasia tarda with progressive arthropathy. A "new" disorder of autosomal recessive inheritance. J. Bone Joint Surg. Br. 64, 442–445 ( 1982).

    Article  CAS  Google Scholar 

  5. Spranger, J., Albert, C., Schilling, F., Bartsocas, C. & Stöss, H. Progressive pseudorheumatoid arthritis of childhood (PPAC). A hereditary disorder simulating rheumatoid arthritis. Eur. J. Pediatr. 140, 34– 40 (1983).

    Article  CAS  Google Scholar 

  6. Teebi, A.S. & Al-Awadi, S.A. Spondyloepiphyseal dysplasia tarda with progressive arthropathy: a rare disorder frequently diagnosed among Arabs. J. Med. Genet. 23, 189– 191 (1986).

    Article  CAS  Google Scholar 

  7. Kozlowski, K., Kennedy, J. & Lewis, I.C. Radiographic features of progressive pseudorheumatoid arthritis. Australas. Radiol. 30, 244– 250 (1986).

    Article  CAS  Google Scholar 

  8. El-Shanti, H. et al. Assignment of gene responsible for progressive pseudorheumatoid dysplasia to chromosome 6 and examination of COL10A1 as candidate gene. Eur. J. Hum. Genet. 6, 251–256 (1998).

    Article  CAS  Google Scholar 

  9. Fischer, J. et al. Genetic linkage of progressive pseudorheumatoid dysplasia to a 3-cM interval of chromosome 6q22. Hum. Genet. 103, 60–64 (1998).

    Article  CAS  Google Scholar 

  10. Pennica, D. et al. WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc. Natl Acad. Sci. USA 95 , 14717–14722 (1998).

    Article  CAS  Google Scholar 

  11. O'Brien, T.P., Yang, G.P., Sanders, L. & Lau, L.F. Expression of cyr61, a growth factor-inducible immediate-early gene. Mol. Cell. Biol. 10, 3569–3577 ( 1990).

    Article  CAS  Google Scholar 

  12. Ryseck, R.-P., Macdonald-Bravo, H., Mattei, M.-G. & Bravo, R. Structure, mapping, and expression of fisp-12, a growth factor-inducible gene encoding a secreted cysteine-rich protein. Cell Growth Differ. 2, 225–233 ( 1991).

    CAS  PubMed  Google Scholar 

  13. Bradham, D.M., Igarashi A., Potter, R.L. & Grotendorst, G.R. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vasular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J. Cell Biol. 114, 1285– 1294 (1991).

    Article  CAS  Google Scholar 

  14. Joliot, V. et al. Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Mol. Cell. Biol. 12, 10– 21 (1992).

    Article  CAS  Google Scholar 

  15. Zhang, R. et al. Identification of rCop-1, a new member of the CCN protein family, as a negative regulator for cell transformation. Mol. Cell. Biol. 18, 6131–6141 ( 1998).

    Article  CAS  Google Scholar 

  16. Hashimoto, Y. et al. Expression of the Elm1 gene, a novel gene of the CCN (connective tissue growth factor, Cyr61/Cef10, and neuroblastoma overexpressed gene) family, suppresses in vivo tumor growth and metastasis of K-1735 murine melanoma cells. J. Exp. Med. 187, 289– 296 (1998).

    Article  CAS  Google Scholar 

  17. Yang, G.P. & Lau, L.F. Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ. 2, 351 –357 (1991).

    CAS  PubMed  Google Scholar 

  18. O'Brien, T.P. & Lau, L.F. Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ. 3, 645–654 (1992).

    CAS  PubMed  Google Scholar 

  19. Kireeva, M.L., Mo, F., Yang, G.P. & Lau, L.F. Cyr61, a product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion. Mol. Cell. Biol. 16, 1326–1334 (1996).

    Article  CAS  Google Scholar 

  20. Martinerie, C., Chevalier, G., Rauscher, F.J. III & Perbal, B. Regulation of nov by WT1: a potential role for nov in nephrogenesis. Oncogene 12, 1479– 1492 (1996).

    CAS  PubMed  Google Scholar 

  21. Wong, M., Kireeva, M.L., Kolesnikova, T.V. & Lau, L.F. Cyr61, a product of a growth factor-inducible immediate-early gene, regulates chondogenesis in mouse limb bud mesenchymal cells. Dev. Biol. 192, 492–508 (1997).

    Article  CAS  Google Scholar 

  22. Grotendorst, G.R. Connective tissue growth factor: a mediator of TGF-β action on fibroblasts. Cytokine Growth Factor Rev. 8, 171– 179 (1997).

    Article  CAS  Google Scholar 

  23. Kothapalli, D., Frazier, K.S., Welply, A., Segarini, P.R. & Grotendorst, G.R. Transforming growth factor B induces anchorage-independent growth of NRK fibroblasts via a connective tissue growth factor-dependent signaling pathway. Cell Growth Differ. 8, 61–68 (1997 ).

    CAS  PubMed  Google Scholar 

  24. Schütze, N. et al. The human analog of murine cystein rich protein 16 ( sic) is a 1,25-dihydroxyvitamin D3 responsive immediate early gene in human fetal osteoblasts: regulation by cytokines, growth factors, and serum. Endocrinology 139, 1761– 1770 (1998).

    Article  Google Scholar 

  25. Erlebacher, A., Filvaroff, E.H., Gitelman, S.E. & Derynck, R. Toward a molecular understanding of skeletal development. Cell 80, 371–378 ( 1995).

    Article  CAS  Google Scholar 

  26. Brigstock, D.R. et al. Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. J. Biol. Chem. 272, 20275–20282 (1997).

    Article  CAS  Google Scholar 

  27. Dale, T.C. Signal transduction by the Wnt family of ligands. Biochem. J. 329, 209–223 (1998).

    Article  CAS  Google Scholar 

  28. Parr, B.A., Avery, E.J., Cygan, J.A. & McMahon, A.P. The classical mouse mutant postaxial hemimelia results from a mutation in the Wnt 7a gene. Dev. Biol. 202, 228–234 (1998).

    Article  CAS  Google Scholar 

  29. Yoo, J.U. et al. The chondrogenic potential of human bone-marrow-derived mesenchymal progenitor cells. J. Bone Joint Surg. Am. 80, 1745–1757 (1998).

    Article  CAS  Google Scholar 

  30. Legius, E., Mulier, M., Van Damme, B. & Fryns, J.P. Progressive pseudorheumatoid arthritis of childhood (PPAC) and normal adult height. Clin. Genet. 44, 152– 155 (1993).

    Article  CAS  Google Scholar 

  31. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 ( 1990).

    Article  CAS  Google Scholar 

  32. Vikkula, M. et al. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 80, 431– 437 (1995).

    Article  CAS  Google Scholar 

  33. Carrel, L. et al. X inactiviation analysis and DNA methylation studies of the ubiquitin activating enzyme E1 and PCTAIRE-1 genes in human and mouse. Hum. Mol. Genet. 5, 391–401 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families for participating in this study, and J. Marcelino, Y. Gong, S. Gregory, P. Modaff, T. Haqqi, B. Johnstone, F.M. Pope and A. Richards for sharing clinical and scientific expertise. This work was supported by NIH grant AR43827 and by a biomedical sciences grant from the March of Dimes Birth Defects Foundation (M.L.W.), grant 45-401.95 from the Swiss National Foundation (A.S.-F.) and a concerted-action grant from the University of Antwerp (W.V.H.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthew L. Warman.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hurvitz, J., Suwairi, W., Van Hul, W. et al. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23, 94–98 (1999). https://doi.org/10.1038/12699

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/12699

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing