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Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33–q34. In the present study, endoglin, a transforming growth factor β (TGF-β) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 base pair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-β receptor complex.

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References

  1. Jahnke, V. Ultrastructure of hereditary telangiectasia. Arch. Otolaryngol. 91, 262–265 (1970).

    Article  CAS  Google Scholar 

  2. Hashimoto, K. & Pritzker, M. Hereditary hemorrhagic telangiectasia: an electron microscope study. Oral Surg., Oral Med., Oral Pathol. 34, 751–768 (1972).

    Article  CAS  Google Scholar 

  3. Braverman, I.M., Keh, A. & Jacobson, B.S. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J. invest. Dermatol. 95, 422–427 (1990).

    Article  CAS  Google Scholar 

  4. Menefee, M.G., Flessa, H.C., Glueck, H.I. & Hogg, S.P. Hereditary hemorrhagic telangiectasia: (Osler-Weber-Rendu disease): an electron microscopic study of the vascular lesions before and after therapy with hormones. Arch. Otolaryngol. 101, 246–251 (1975).

    Article  CAS  Google Scholar 

  5. McDonald, M.T. et al. A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33–34. Nature Genet. 6, 197–204 (1994).

    Article  CAS  Google Scholar 

  6. Shovlin, C. et al. A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nature Genet. 6, 205–209 (1994).

    Article  CAS  Google Scholar 

  7. McAllister, K.A. et al. Genetic heterogeneity in hereditary hemorrhagic telangiectasia: possible correlation with clinical phenotype. J. med. Genet. 31, 927–932 (1994).

    Article  CAS  Google Scholar 

  8. Porteous, M.E.M. et al. Genetic heterogeneity in hereditary haemorrhagic telangiectasia. J. med. Genet. 31, 925–926 (1994).

    Article  CAS  Google Scholar 

  9. Heutink, P. et al. Linkage of hereditary hemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity. J. med. Genet. 31, 933–936 (1994).

    Article  CAS  Google Scholar 

  10. Greenspan, D.S. et al. COL5A1: Fine genetic mapping and exclusion as candidate gene in families with nail-patella syndrome, tiberous sclerosis 1, hereditary hemorrhagic telangiectasia and Ehlers-Danlos syndrome type II. Genomics (in the press).

  11. Gougos, A. & Letarte, M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J. biol. Chem. 265, 8361–8364 (1990).

    CAS  PubMed  Google Scholar 

  12. Cheifetz, S. et al. Endoglin is a component of the transforming growth factor-b receptor system in human endothelial cells. J. biol. Chem. 267, 19027–19030 (1992).

    CAS  PubMed  Google Scholar 

  13. Yamashita, H. et al. Endoglin forms a heteromeric complex with the signaling receptors for transforming growth factor-β. J. biol. Chem. 269, 1995–2001 (1994).

    CAS  PubMed  Google Scholar 

  14. Massagué, J., Attisano, L. & Wrana, J.L. The TGF-β family and its composite receptors. Trends cell Biol. 4, 172–178 (1994).

    Article  Google Scholar 

  15. Fernández-Ruiz, E., St-Jacques, S., Bellón, T., Letarte, M. & Bernabeu, C. Assignment of the human endoglin gene (END) to 9q34–qter. Cytogenet. Cell Genet. 64, 204–207 (1993).

    Article  Google Scholar 

  16. Pilz, A., Woodward, K., Peters, J., Povey, S & Abbot, C. Comparative mapping of 38 human chromosome 9 loci in the laboratory mouse. Abstract from the third international workshop on chromosome 9. Ann. hum. Genet. 58, 231–232 (1994).

    Google Scholar 

  17. Povey, S. et al. Report on the third international workshop on human chromosome 9. Ann. hum. Genet. 58, 177–199 (1994).

    Article  CAS  Google Scholar 

  18. Leversha, M.A., Carter, N.P. & Ferguson-Smith, M.A. Physical mapping in 9q using fluorescence in situhybridization. Abstract from the third international workshop on chromosome 9. Ann. hum. Genet. 58, 224 (1994).

    Google Scholar 

  19. Lastres, P. et al. Regulated expression on human macrophages of endoglin, an RGD containing surface antigen. Eur.J.Immunol. 22, 393–397 (1992).

    Article  CAS  Google Scholar 

  20. Gougos, A. et al. Identification of distinct epitopes of endoglin, an RGD-containing glycoprotein of endothelial cells, leukemic cells, and syncytiotrophoblasts. Int. Immunol. 4, 83–92 (1992).

    Article  CAS  Google Scholar 

  21. St-Jacques, S., Cymerman, U., Pece, N. & Letarte, M. Molecular characterization and in situ localization of murine endoglin reveal that it is a transforming growth factor-β binding protein of endothelial and stromal cells. Endocrinology 134, 2645–2657 (1994).

    Article  CAS  Google Scholar 

  22. Madri, J.A. et al. Interactions of matrix components and soluble factors in vascular responses to injury. Modulation of cell phenotype. in Endothelial cell dysfunctions (eds Simionescu, N. & Simionescu, M.) (Plenum Press, New York, (1992).

    Google Scholar 

  23. Jennings, J.C., Mohan, S., Linkhart, T.A., Widstrom, R. & Baylink, D.J. Comparison of the biological actions of TGF beta-1 and TGF beta-2: differential activity in endotheiial cells. J. cell. Physiol. 137, 167–172 (1988).

    Article  CAS  Google Scholar 

  24. Luscinkas, F.W. & Lawler, J. Integrins as dynamics regulators of vascular function. FASEB J. 8, 929–938 (1994).

    Article  Google Scholar 

  25. Wrana, J.L. et al. TGF-β signals through a heteromeric protein kinase receptor complex. Cell 71, 1003–1014 (1992).

    Article  CAS  Google Scholar 

  26. Wrana, J.L., Attisano, A., Wieser, R., Ventura, F., Massagué, J. Mechanisms of activation of the TGF-β receptor. Nature 370, 341–347 (1994).

    Article  CAS  Google Scholar 

  27. López-Casillas, F. et al. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-β receptor. Cell 67, 785–795 (1991).

    Article  Google Scholar 

  28. Wang, X.-F. et al. Expression cloning and characterization of the TGF-β type III receptor. Cell 67, 797–805 (1991).

    Article  CAS  Google Scholar 

  29. López-Casillas, F., Wrana, J.L. & Massagué, J. Betaglycan presents ligand to the TGF-β signaling receptor. Cell 73, 1435–1444 (1993).

    Article  Google Scholar 

  30. Cheifetz, S. et al. Distinct transforming growth factor-β (TGF-β) receptor subsets as determinants of cellular responsiveness to three TGF-β isoforms. J. biol. Chem. 265, 20533–20538 (1990).

    CAS  Google Scholar 

  31. Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  Google Scholar 

  32. Kulkarni, A.B. et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. natn. Acad. Sci. U.S.A. 90, 770–774 (1993).

    Article  CAS  Google Scholar 

  33. Letterio, J.J. et al. Maternal rescue of transforming growth factor-β1 null mice. Science 264, 1936–1938 (1994).

    Article  CAS  Google Scholar 

  34. Mathew, S. et al. Transforming growth factor gene TGFBR2 maps to human chromosome band 3p22. Genomics 20, 114–115 (1994).

    Article  CAS  Google Scholar 

  35. Blanchard, M.M., Taillon-Miller, P., Nowotny, P. & Nowotny, V. PCR buffer optimization with uniform temperature regimen to facilitate automation. PCR Meth. Applic. 2, 234–240 (1993).

    Article  CAS  Google Scholar 

  36. Bellón, T. et al. Identification and expression of two forms of the human transforming growth-factor-β binding-protein endoglin with distinct cytoplasmic regions. Eur. J. Immunol. 23, 2340–2345 (1993).

    Article  Google Scholar 

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McAllister, K., Grogg, K., Johnson, D. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8, 345–351 (1994). https://doi.org/10.1038/ng1294-345

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