Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B (original) (raw)

Nature Genetics volume 24, pages 275–278 (2000)Cite this article

Abstract

Inherited limb malformations provide a valuable resource for the identification of genes involved in limb development1,2. Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies3 and characterized by terminal deficiency of the fingers and toes. In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication4,5,6,7,8. The BDB1 locus was previously mapped to chromosome 9q22 within an interval of 7.5 cM (refs 9,10). Here we describe mutations in ROR2, which encodes the orphan receptor tyrosine kinase ROR2 (ref. 11), in three unrelated families with BDB1. We identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7–amino-acid segment of the 943–amino-acid protein, all of which predict truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggests that they confer a specific gain of function. We obtained further evidence for this by demonstrating that two patients heterozygous for 9q22 deletions including ROR2 do not exhibit BDB. Expression of the mouse orthologue, Ror2, early in limb development indicates that BDB arises as a primary defect of skeletal patterning.

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References

  1. Innis, J.W. & Mortlock, D.P. Limb development: molecular dysmorphology is at hand! Clin. Genet. 53, 337– 348 (1998).
    Article CAS Google Scholar
  2. Manouvrier-Hanu, S., Holder-Espinasse, M. & Lyonnet, S. Genetics of limb anomalies in humans. Trends Genet. 15, 409–417 ( 1999).
    Article CAS Google Scholar
  3. Fitch, N. Classification and identification of inherited brachydactylies. J. Med. Genet. 16, 36–44 (1979).
    Article CAS Google Scholar
  4. MacArthur, J.W. & McCullough, E. Apical dystrophy: an inherited defect of hands and feet. Hum. Biol. 4 , 179–207 (1932).
    Google Scholar
  5. Malloch, J.D. Brachydactyly and symbrachydactyly. Ann. Hum. Genet. 22, 36–37 (1957).
    Article CAS Google Scholar
  6. Degenhardt, K.-H. & Geipel, G. Dominant erbliche Perodaktylien in 4 generationen einer Sippe. Z. menschl. Vererb.- u. Konstitutionslehre 32, 227–307 (1954).
    Google Scholar
  7. Battle, H.I., Walker, N.F. & Thompson, M.W. Mackinder's hereditary brachydactyly: phenotypic, radiological, dermatoglyphic and genetic observations in an Ontario family . Ann. Hum. Genet. 36, 415– 424 (1973).
    Article CAS Google Scholar
  8. Houlston, R.S. & Temple, I.K. Characteristic facies in type B brachydactyly. Clin. Dysmorphol. 3, 224– 227 (1994).
    CAS PubMed Google Scholar
  9. Gong, Y. et al. Brachydactyly type B: clinical description, genetic mapping to chromosome 9q, and evidence for a shared ancestral mutation. Am. J. Hum. Genet. 64, 570–577 (1999).
    Article CAS Google Scholar
  10. Oldridge, M. et al. Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity. Am. J. Hum. Genet. 64, 578–585 (1999).
    Article CAS Google Scholar
  11. Masiakowski, P. & Carroll, R.D. A novel family of cell surface receptors with tyrosine kinase-like domain. J. Biol. Chem. 267, 26181–26190 (1992).
    CAS PubMed Google Scholar
  12. 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 Google Scholar
  13. Oishi, I. et al. Spatio-temporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system. Genes Cells 4, 41 –56 (1999).
    Article CAS Google Scholar
  14. Deloukas, P. et al. A physical map of 30,000 human genes. Science 282, 744–746 (1998).
    Article CAS Google Scholar
  15. Forrester, W.C., Dell, M., Perens, E. & Garriga, G.A.C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division. Nature 400, 881– 885 (1999).
    Article CAS Google Scholar
  16. Wilson, C., Goberdhan, D.C.I. & Steller, H. Dror, a potential neurotrophic receptor gene, encodes a Drosophila homolog of the vertebrate Ror family of Trk-related receptor tyrosine kinases. Proc. Natl Acad. Sci. USA 90, 7109–7113 (1993).
    Article CAS Google Scholar
  17. Oishi, I. et al. A novel Drosophila receptor tyrosine kinase expressed specifically in the nervous system. J. Biol. Chem. 272, 11916–11923 (1997).
    Article CAS Google Scholar
  18. Pawson, T. Protein modules and signalling networks. Nature 373 , 573–580 (1995).
    Article CAS Google Scholar
  19. Afzal, A.R. et al. Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22. Hum. Genet. (in press).
  20. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152– 154 (1996).
    Article CAS Google Scholar
  21. Blair, I.P., Hulme, D., Dawkins, J.L. & Nicholson, G.A. A YAC-based transcript map of human chromosome 9q22.1–q22.3 encompassing the loci for hereditary sensory neuropathy type I and multiple self-healing squamous epithelioma. Genomics 51, 277– 281 (1998).
    Article CAS Google Scholar
  22. Wilkie, A.O.M. et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nature Genet. 9, 165–172 (1995).
    Article CAS Google Scholar
  23. Oldridge, M. et al. Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. Hum. Mol. Genet. 6, 137–143 (1997).
    Article CAS Google Scholar

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Acknowledgements

We thank E. Jowitt, J. Loughlin, H. Santos and K. Temple for their help with earlier stages of this work; S. Butler and N. Elanko for technical assistance; G. Morriss-Kay for discussions; and D. Weatherall for support. The Chromosome Abnormality Database is funded by South East NHSE. This work was funded by Wellcome Trust awards to M.O. and A.O.M.W.

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Authors and Affiliations

  1. Institute of Molecular Medicine, John Radcliffe Hospital , Oxford, UK
    Michael Oldridge & Andrew O.M. Wilkie
  2. Instituto de Genética Médica, Porto, Portugal
    Ana M Fortuna
  3. Institut für Humangenetik, Rheinische Friedrich-Wilhelms-Universität , Bonn, Germany
    Monika Maringa & Peter Propping
  4. S.W. Thames Regional Genetics Service, St George's Hospital Medical School, Cranmer Terrace, London, UK
    Sahar Mansour
  5. Northern Region Genetics Service, Royal Victoria Infirmary , Newcastle upon Tyne, UK
    Christine Pollitt
  6. Regeneron Pharmaceuticals, Inc, Tarrytown , New York, USA
    Thomas M. DeChiara, Robert B. Kimble, David M. Valenzuela & George D. Yancopoulos

Authors

  1. Michael Oldridge
  2. Ana M Fortuna
  3. Monika Maringa
  4. Peter Propping
  5. Sahar Mansour
  6. Christine Pollitt
  7. Thomas M. DeChiara
  8. Robert B. Kimble
  9. David M. Valenzuela
  10. George D. Yancopoulos
  11. Andrew O.M. Wilkie

Corresponding author

Correspondence toAndrew O.M. Wilkie.

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Oldridge, M., M Fortuna, A., Maringa, M. et al. Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.Nat Genet 24, 275–278 (2000). https://doi.org/10.1038/73495

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