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.

  • Article
  • Published:

Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome

Nature Genetics volume 12, pages 130–136 (1996)Cite this article

Abstract

Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development, which has been localized to chromosome 5q32–33.1. In the present study, the isolation of new polymorphic markers has allowed the identification of overlapping recombination events in two affected individuals. Extension of the transcription map of the critical region proximally has resulted in the isolation of a new gene (which has been named Treacle) of unknown function. The identification of different mutations in five unrelated families, all of which would result in premature termination of the predicted protein, indicates that the Treacher Collins syndrome gene has been positionally cloned.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Johnston, M.C. & Bronsky, P.T. Embryonic craniofacial development. Prog. Clin. Biol. Res. 337, 99–115 (1991).

    Google Scholar 

  2. Gorlin, R.J., Cohen, M.M. & Levin, L.S. Syndromes of the Head and Neck. (Oxford University Press, Oxford, 1990).

    Google Scholar 

  3. Treacher Collins, E. Cases with symmetrical congenital notches in the outer part of each lid and defective development of the malar bones. Trans Ophthalmol. Soc. UK. 20, 190–192 (1900).

    Google Scholar 

  4. Franceschetti, A. & Klein, D. Mandibulo-facial dysostosis: New hereditary syndrome. Acta Ophthamol. 27, 143–224 (1949).

    CAS  Google Scholar 

  5. Jones, K.L., Smith, D.W., Harvey, M.A., Hall, B.D. & Quan, L. Older paternal age and fresh gene mutation: data on additional disorders. J. Pediatr. 86, 84–88 (1975).

    Article  CAS  Google Scholar 

  6. Phelps, P.D., Poswillo, D. & Lloyd, G.A.S. The ear deformities in mandibulofacial dysostosis. Clin. Otolaryngol. 6, 15–28 (1981).

    Article  CAS  Google Scholar 

  7. Rovin, S., Dachi, S.F., Borenstein, D.B. & Cotter, W.B. Mandibulofacial dysostosis, a familial study of five generations. J. Pediatr. 65, 215–221 (1964).

    Article  CAS  Google Scholar 

  8. Fazen, L.E., Elmore, J. & Nadler, H.L. Mandibulo-facial dysostosis (Treacher Collins syndrome). Am. J. Dis. Child. 113, 406–410 (1967).

    Article  Google Scholar 

  9. Dixon, M.J., Marres, H.A.M., Edwards, S., Dixon, J. & Cremers, C.W.R.J. Treacher Collins syndrome: Correlation between clinical and genetic linkage studies. Clin. Dysmorph. 3, 96–103 (1994).

    Article  CAS  Google Scholar 

  10. Marres, H.A.M., Cremers, C.W.R.J., Dixon, M.J., Huygen, R.L.M. & Joosten, F.B.M. The Treacher Collins syndrome: A clinical, radiological and genetic linkage study on two pedigrees. Archs. Otol. 121, 509–514 (1995).

    Article  CAS  Google Scholar 

  11. Poswillo, D. The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis). Br. J. Oral Surg. 13, 1–26 (1975).

    Article  CAS  Google Scholar 

  12. Wiley, M.J., Cauwenbergs, P. & Taylor, I.M. Effects of retinoic acid on the development of the facial skeleton in hamsters; early changes involving neural crest cells. Acta. Anat. 116, 180–192 (1983).

    Article  CAS  Google Scholar 

  13. Sulik, K.K., Johnston, M.C., Smiley, S.J., Speight, H.S. & Jarvis, B.E. Mandibulofacial dysostosis (Treacher Collins syndrome): a new proposal for its pathogenesis. Am. J. Med. Genet. 27, 359–372 (1987).

    Article  CAS  Google Scholar 

  14. Mandel, J.L. Trinucleotide diseases on the rise. Nature Genet. 7, 453–455 (1994).

    Article  CAS  Google Scholar 

  15. Dixon, M.J. et al. The gene for Treacher Collins syndrome maps to the long arm of chromosome 5. Am. J. Hum. Genet. 40, 17–22 (1991).

    Google Scholar 

  16. Jabs, E.W. et al. Mapping the Treacher Collins syndrome locus to 5q31.3-q33.3. Genomics 11, 193–198 (1991).

    Article  CAS  Google Scholar 

  17. Loftus, S.K. et al. A combined genetic and radiation hybrid map surrounding the Treacher Collins syndrome locus on chromosome 5q. Hum. Mol. Genet. 2, 1785–1792 (1993).

    Article  CAS  Google Scholar 

  18. Edery, P. et al. Apparent genetic homogeneity of the Treacher Collins-Franceschetti syndrome. Am. J. Med. Genet. 52, 174–177 (1994).

    Article  CAS  Google Scholar 

  19. Dixon, M.J. et al. Narrowing the position of the Treacher Collins syndrome locus to a small interval between three new microsatellite markers at 5q32-33.1. Am. J. Hum. Genet. 52, 907–914 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Dixon, J. et al. A yeast artificial chromosome contig encompassing the Treacher Collins syndrome critical region at 5q31.3–32. Am. J. Hum. Genet. 55, 372–378 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Loftus, S.K. et al. Transcriptional map of the Treacher Collins candidate gene region. Genome Res. (in the press).

  22. Jabs, E.W. et al. Genetic and physical mapping of the Treacher Collins syndrome locus with respect to loci in the chromosome 5q3 region. Genomics 18, 7–13 (1993).

    Article  CAS  Google Scholar 

  23. Breathnach, R. & Chambon, P. Organization and expression of eukaryotic split genes coding for proteins. Annu. Rev. Biochem. 50, 349–383 (1981).

    Article  CAS  Google Scholar 

  24. Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common form of dwarfism, achondroplasia. Cell 78, 11–20 (1994).

    Article  Google Scholar 

  25. Hastabacka, J. The diastrophic dysplasia gene encodes a novel sulfate transporter: Positional cloning by fine-structure linkage disequilibrium mapping. Cell 78, 1073–1087 (1994).

    Article  Google Scholar 

  26. Bonner, C.A., Loftus, S.K. & Wasmuth, J.J., Isolation, characterization, and precise physical localization of human CDX1, a caudal-type homeobox gene. Genomics 28, 206–211 (1995).

    Article  CAS  Google Scholar 

  27. Dixon, J. et al. Cloning of the human heparan sulfate-N-deacetylase/N-sulfotransferase gene from the Treacher Collins syndrome candidate region at 5q32–33.1. Genomics 26, 239–244 (1995).

    Article  CAS  Google Scholar 

  28. Del Mastro, R. et al. Human chromosome-specific cDNA libraries. New tools for gene identification and genome annotation. Genome Res. 5, 185–194 (1995).

    Article  CAS  Google Scholar 

  29. Li, S.H. et al. Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron 11, 985–993 (1993).

    Article  CAS  Google Scholar 

  30. Fisher, E. & Scambler, P.J. Human haploinsufficiency - one for sorrow, two for joy. Nature Genet. 7, 5–7 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Baldwin, C.T., Hoth, C.F., Amos, J.A., da-Silva, E.G. & Milunsky, A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature 355, 637–638 (1992).

    Article  CAS  Google Scholar 

  33. Gladwin, A.J., Dixon, J., Loftus, S.K., Wasmuth, J.J. & Dixon, M.J. Genomic organization of the human heparan sulfate-N-deacetylase/N-sulfotransferase gene: Exclusion from a causative role in the pathogenesis of Treacher Collins syndrome. Genomics (in the press).

  34. Dixon, M.J. et al. Association of Treacher Collins syndrome and translocation (6:16)(p21.31;p13.11) exclusion of the locus from these candidate regions. Am. J. Hum. Genet. 48, 274–280 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Balestrazzi, P., Baeteman, M.A., Mattei, M.G. & Mattei, J.F. Franceshetti syndrome in a child with a de novo balanced translocation (5;13)(q11;p11) and significant decrease of hexosaminidase B. Hum. Genet. 64, 305–308 (1983).

    Article  CAS  Google Scholar 

  36. Jabs, E.W. et al. Chromosomal deletion 4p15.32–p14 in a Treacher Collins syndrome patient: Exclusion of the disease locus from and mapping of anonymous DNA sequences to this region. Genomics 11, 188–192 (1991).

    Article  CAS  Google Scholar 

  37. Arn, P.H., Mankinen, C. & Jabs, E.W. Mild mandibulofacial dysostosis in a child with a deletion of 3p. Am. J. Med. Genet. 46, 534–536 (1993).

    Article  CAS  Google Scholar 

  38. Dixon, M.J. et al. Genetic and physical mapping of the Treacher Collins syndrome locus: Refinement of the localization to chromosome 5q32–33.2. Hum. Mol. Genet. 1, 249–253 (1992).

    Article  CAS  Google Scholar 

  39. Sambrook, J., Fritsch, E.F. & Maniatis, T. In Molecular cloning: a laboratory manual. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

  40. Sanger, F., Nicklen, S. & Coulson, A.R. DNA sequencing with chain terminating inhibitors. Proc. Nat. Acad. Sci. USA 74, 5463–5467 (1977).

    Article  CAS  Google Scholar 

  41. Artschul, S.F., Gish, W., Miller, W., Myer, E.W. & Lipman, D.J. Basic local alignment search tool. J. Molec. Biol. 215, 403–410 (1990).

    Article  Google Scholar 

  42. Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).

    Article  CAS  Google Scholar 

  43. Rashtchian, A., Buchman, G.W., Schuster, D.M. & Berninger, M.S. Uracil DNA Glycosylase mediated cloning of polymerase chain reaction-amplified DNA: Application to genomic and cDNA cloning. Anal. Biochem. 206, 91–97 (1992).

    Article  CAS  Google Scholar 

  44. Feinberg, A.P. & Vogelstein, B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132, 6–13 (1983).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Jill Dixon, Sara J. Edwards and Amanda J. Gladwin: J.D., S.J.E. & A.J.G. contributed equally to the work of Group 1.

Authors and Affiliations

  1. Group 1: School of Biological Sciences and Departments of Dental Medicine and Surgery, University of Manchester, 3.239, Stopford Building, Oxford Road, Manchester, M13 9PT, UK

    Jill Dixon, Sara J. Edwards, Amanda J. Gladwin & Michael J. Dixon

  2. Group 2: Department of Biological Chemistry, College ofMedicine, University of California, Irvine, California, 92717, USA

    Stacie K. Loftus, Cynthia A. Bonner, Kathryn Koprivnikar  & John J. Wasmuth

Authors
  1. The Treacher Collins Syndrome Collaborative Group
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jill Dixon
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Sara J. Edwards
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Amanda J. Gladwin
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Michael J. Dixon
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Stacie K. Loftus
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Cynthia A. Bonner
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Kathryn Koprivnikar
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. John J. Wasmuth
    View author publications

    You can also search for this author inPubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

The Treacher Collins Syndrome Collaborative Group, Dixon, J., Edwards, S. et al. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat Genet 12, 130–136 (1996). https://doi.org/10.1038/ng0296-130

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0296-130

This article is cited by

Search

Advanced 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