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.

The genetic basis for skeletal diseases

Abstract

We walk, run, work and play, paying little attention to our bones, their joints and their muscle connections, because the system works. Evolution has refined robust genetic mechanisms for skeletal development and growth that are able to direct the formation of a complex, yet wonderfully adaptable organ system. How is it done? Recent studies of rare genetic diseases have identified many of the critical transcription factors and signalling pathways specifying the normal development of bones, confirming the wisdom of William Harvey when he said: “nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path”.

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: Skeletal development.
Figure 2: Differentiation factors in chondrocytic and osteoblastic differentiation.
Figure 3: Mouse and human phenotypes caused by mutations affecting skeletal patterning and differentiation.
Figure 4: Genes causing different types of Waardenburg syndrome and their role in osteoclast differentiation.

References

  1. Olsen, B. R., Reginato, A. M. & Wang, W. Bone development. Annu. Rev. Cell Dev. Biol. 16, 191–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Royce, P. & Steinmann, B. (eds) Connective Tissue and its Heritable Disorders: Molecular, Genetic, and Medical Aspects (Wiley, New York, 2002).

    Book  Google Scholar 

  3. Wilkie, A. O., Oldridge, M., Tang, Z. & Maxson, R. E. Jr Craniosynostosis and related limb anomalies. Novartis Found. Symp. 232, 122–133, 133–143 (2001).

    CAS  PubMed  Google Scholar 

  4. Hall, C. M. International nosology and classification of constitutional disorders of bone. Am. J. Med. Genet. 113, 65–77 (2002).

    Article  PubMed  Google Scholar 

  5. Mundlos, S. & Olsen, B. R. Heritable diseases of the skeleton. Part I: Molecular insights into skeletal development—transcription factors and signaling pathways. FASEB J. 11, 125–132 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Foster, J. W. et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372, 525–530 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Wagner, T. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79, 1111–1120 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Bi, W. et al. Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc. Natl Acad. Sci. USA 98, 6698–6703 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. & de Crombrugghe, B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 16, 2813–2828 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Smits, P. et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev. Cell 1, 277–290 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Bell, D. M. et al. SOX9 directly regulates the type-II collagen gene. Nature Genet. 16, 174–178 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L. & Karsenty, G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747–754 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Mundlos, S. et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773–779 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Kim, I. S., Otto, F., Zabel, B. & Mundlos, S. Regulation of chondrocyte differentiation by Cbfa1. Mech. Dev. 80, 159–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Kundu, M. et al. Cbfβ interacts with Runx2 and has a critical role in bone development. Nature Genet. 32, 639–644 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Miller, J. et al. The core-binding factor β subunit is required for bone formation and hematopoietic maturation. Nature Genet. 32, 645–649 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Yoshida, C. A. et al. Core-binding factor β interacts with Runx2 and is required for skeletal development. Nature Genet. 32, 633–638 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Nakashima, K. et al. The novel zinc finger-containing transcription factor Osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29. (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Tassabehji, M. et al. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature 355, 635–636 (1992).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Mansouri, A., Pla, P., Larue, L. & Gruss, P. Pax3 acts cell autonomously in the neural tube and somites by controlling cell surface properties. Development 128, 1995–2005 (2001).

    CAS  PubMed  Google Scholar 

  23. Bober, E., Franz, T., Arnold, H. H., Gruss, P. & Tremblay, P. Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells. Development 120, 603–612 (1994).

    CAS  PubMed  Google Scholar 

  24. Epstein, D. J., Vekemans, M. & Gros, P. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell 67, 767–774 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Hodgkinson, C. A. et al. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 74, 395–404 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Tassabehji, M., Newton, V. E. & Read, A. P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nature Genet. 8, 251–255 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Steingrimsson, E. et al. Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences. Nature Genet. 8, 256–263 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Weilbaecher, K. N. et al. Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitfmi/mi mice. Mol. Cell 8, 749–758 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Steingrimsson, E. et al. Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development. Proc. Natl Acad. Sci. USA 99, 4477–4482 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. Motyckova, G. et al. Linking osteopetrosis and pycnodysostosis: regulation of cathepsin K expression by the microphthalmia transcription factor family. Proc. Natl Acad. Sci. USA 98, 5798–5803 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  31. Palmeirim, I., Henrique, D., Ish-Horowicz, D. & Pourquie, O. Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell 91, 639–648 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. McGrew, M. J., Dale, J. K., Fraboulet, S. & Pourquie, O. The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos. Curr. Biol. 8, 979–982 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Bulman, M. P. et al. Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature Genet. 24, 438–441 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Kusumi, K. et al. The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nature Genet. 19, 274–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Dunwoodie, S. L. et al. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development 129, 1795–1806 (2002).

    CAS  PubMed  Google Scholar 

  36. Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R. L. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394, 377–381 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Zhang, N. & Gridley, T. Defects in somite formation in lunatic fringe-deficient mice. Nature 394, 374–377 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  38. Oda, T. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature Genet. 16, 235–242 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature Genet. 16, 243–251 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Xue, Y. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum. Mol. Genet. 8, 723–730 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. McCright, B., Lozier, J. & Gridley, T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 129, 1075–1082 (2002).

    CAS  PubMed  Google Scholar 

  42. Vortkamp, A., Gessler, M. & Grzeschik, K. H. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540 (1991).

    Article  ADS  CAS  PubMed  Google Scholar 

  43. Kohlhase, J., Wischermann, A., Reichenbach, H., Froster, U. & Engel, W. Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nature Genet. 18, 81–83 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Muragaki, Y., Mundlos, S., Upton, J. & Olsen, B. R. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 272, 548–551 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Hui, C. C. & Joyner, A. L. A mouse model of Greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nature Genet. 3, 241–246 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Thien, H. & Ruther, U. The mouse mutation Pdn (Polydactyly Nagoya) is caused by the integration of a retrotransposon into the Gli3 gene. Mamm. Genome 10, 205–209 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Johnson, K. R. et al. A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly. Hum. Mol. Genet. 7, 1033–1038 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. McCready, M. E. et al. A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved. Hum. Genet. 111, 368–375 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Oldridge, M. et al. Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nature Genet. 24, 275–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. DeChiara, T. M. et al. Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. Nature Genet. 24, 271–274 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Afzal, A. R. et al. Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nature Genet. 25, 419–422 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. van Bokhoven, H. et al. Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nature Genet. 25, 423–426 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Polinkovsky, A. et al. Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nature Genet. 17, 18–19 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Storm, E. E. et al. Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ-superfamily. Nature 368, 639–643 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  55. Thomas, J. T. et al. A human chondrodysplasia due to a mutation in a TGF-β superfamily member. Nature Genet. 12, 315–317 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Gong, Y. et al. Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nature Genet. 21, 302–304 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Brunet, L. J., McMahon, J. A., McMahon, A. P. & Harland, R. M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280, 1455–1457 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  58. Schipani, E., Kruse, K. & Jüppner, H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268, 98–100 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  59. Jobert, A. S. et al. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J. Clin. Invest. 102, 34–40 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hopyan, S. et al. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nature Genet. 30, 306–310 (2002).

    Article  PubMed  Google Scholar 

  61. Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335–342 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Bellus, G. A. et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nature Genet. 10, 357–359 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Tavormina, P. L. et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nature Genet. 9, 321–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Tavormina, P. L. et al. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am. J. Hum. Genet. 64, 722–731 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Naski, M. C., Wang, Q., Xu, J. & Ornitz, D. M. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nature Genet. 13, 233–237 (1996).

    Article  CAS  PubMed  Google Scholar 

  66. Ohbayashi, N. et al. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 16, 870–879 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. & Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G. & Ornitz, D. M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet. 12, 390–397 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Minina, E., Kreschel, C., Naski, M. C., Ornitz, D. M. & Vortkamp, A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev. Cell 3, 439–449 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Belin, V. et al. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nature Genet. 19, 67–69 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Rao, E. et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nature Genet. 16, 54–63 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Shears, D. J. et al. Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation. Am. J. Med. Genet. 110, 153–157 (2002).

    Article  PubMed  Google Scholar 

  73. Munns, C. F. et al. Histopathological analysis of Leri-Weill dyschondrosteosis: disordered growth plate. Hand Surg. 6, 13–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Ross, J. L. et al. Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or hypochondroplasia. Am. J. Med. Genet. 116, 61–65. (2003).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Elazar Zelzer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zelzer, E., Olsen, B. The genetic basis for skeletal diseases. Nature 423, 343–348 (2003). https://doi.org/10.1038/nature01659

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01659

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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