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Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2

Nature Genetics volume 13, pages 189–195 (1996)Cite this article

Abstract

Hereditary haemorrhagic telangiectasia, or Osler–Rendu–Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38–Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALKI), a member of the serine–threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.

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References

  1. Guttmacher, A.E., McKinnon, W.C. & Upton, M.D. Hereditary hemorrhagic telangiectasia: a disorder in search of the genetics community. Am. J. Med. Genet. 52, 252–253 (1994).

    Article  CAS  Google Scholar 

  2. Guttmacher, A.E., Marchuk, D.A. & White, R.I. Current concepts: Hereditary hemorrhagic telangiectasia. New Engl. J. Med. 333, 918–924 (1995).

    Article  CAS  Google Scholar 

  3. 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 

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

    Article  CAS  Google Scholar 

  5. McAllister, K.A. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genet. 8, 345–351 (1994).

    Article  CAS  Google Scholar 

  6. 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 

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

    CAS  PubMed  Google Scholar 

  8. McAllister, K.A. et al. Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type 1 suggest a dominant-negative effect of receptor function. Hum. Mol. Genet. 4, 1983–1985 (1995).

    Article  CAS  Google Scholar 

  9. 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 

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

    Article  CAS  Google Scholar 

  11. 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 

  12. Berg, J.N., Guttmacher, A.E., Marchuk, D.A. & Porteous, M.E.M. Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J. Med. Genet. 33, 256–257 (1996).

    Article  CAS  Google Scholar 

  13. Vincent, P. et al. A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q. Hum. Mol. Genet. 4, 945–949 (1995).

    Article  CAS  Google Scholar 

  14. Johnson, D.W. et al. A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12. Genome Res. 5, 21–28 (1995).

    Article  CAS  Google Scholar 

  15. Attisano, L. et al. Identification of human activin and TGF-β type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 75, 671–680 (1993).

    Article  CAS  Google Scholar 

  16. ten Dijke, P. et al. Serine/threonine kinase receptors. Prog. Growth Factor Res. 5, 55–72 (1994).

    Article  CAS  Google Scholar 

  17. ten Dijke, P. et al. Characterization of type I receptors for transforming growth factor-b and activin. Science. 264, 101–104 (1994).

    Article  CAS  Google Scholar 

  18. Miyazono, K., ten Dijke, P., Yamashita, H. & Heldin, C.-H., Signal transduction via serine/threonine kinase receptors. Semin. Cell Bio. 5, 389–398 (1994).

    Article  CAS  Google Scholar 

  19. Mathews, L.S. Activin receptors and cellular signaling by the receptor serine kinase family. Endocrine Rev. 15, 310–325 (1994).

    Article  CAS  Google Scholar 

  20. Gyapay, G. et al. The 1993–94 Genethon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

    Article  CAS  Google Scholar 

  21. Kucherlapati, R., Craig, I. & Marynen, P. Report of the second international workshop on human chromosome 12 mapping 1994. Cytogenet. Cell Genet. 67, 246–264 (1994).

    Article  CAS  Google Scholar 

  22. Carcamo, J. et al. Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor β and activin. Mol. Cell. Biol. 14, 3810–3821 (1994).

    Article  CAS  Google Scholar 

  23. ten Dijke, P. et al. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene. 8, 2879–2887 (1993).

    CAS  PubMed  Google Scholar 

  24. Hanks, S.K. & Hunter, T. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).

    Article  CAS  Google Scholar 

  25. Choi, M.E. & Ballermann, B.J. Inhibition of capillary morphogenesis and associated apoptosis by dominant negative mutant transforming growth factor-β receptors. J. Biol. Chem. 270, 21144–21150 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. 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 

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

    Article  Google Scholar 

  29. Krauter, K. et al. A second-generation YAC contig map of human chromosome 12. Nature. 377, 321–333 (1995).

    CAS  PubMed  Google Scholar 

  30. Struewing, J.P. et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nature Genet. 11, 198–200 (1995).

    Article  CAS  Google Scholar 

  31. Franzen, P. et al. Cloning of a TGF-β type I receptor that forms a heteromeric complex with the TGF-β type II receptor. Cell. 75, 681–692 (1993).

    Article  CAS  Google Scholar 

  32. Wrana, J.L. et al. Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. Mol. Cell. Biol. 14, 944–950 (1994).

    Article  CAS  Google Scholar 

  33. Xie, T., Finelli, A.L. & Padgett, R.W., Drosophila saxophone gene encodes a serine-threonine kinase receptor of the TGF-β superfamily. Science. 263, 1756–1759 (1994).

    Article  CAS  Google Scholar 

  34. Brummel, T.J. et al. Characterization and relationship of Dpp receptors encoded by the saxophone and thick veins genes in Drosophila. Cell. 78, 251–261 (1994).

    Article  CAS  Google Scholar 

  35. Wrana, J.L. et al. Mechanism of activation of the TGF-β receptor. Nature. 370, 341–347 (1994).

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Genetics, Duke University Medical Center, Box 3175, Durham, North Carolina, 27710, USA

    D.W. Johnson, J.N. Berg, M.A. Baldwin, C.J. Gallione, T.T. Stenzel & D.A. Marchuk

  2. Department of Human Genetics, University of Edinburgh, Edinburgh, EH4 2XU, UK

    J.N. Berg & M.E.M. Porteous

  3. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, 10461, USA

    I. Marondel, S.-J. Yoon & R. Kucherlapati

  4. Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, USA

    T.T. Stenzel

  5. Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, North Carolina, 27710, USA

    M. Speer & M.A. Pericak-Vance

  6. Department of Immunology, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4AA, UK

    A. Diamond

  7. Department of Pediatrics, University of Vermont, Burlington, VT, 05401, USA

    A.E. Guttmacher

  8. Departmentof Medicine, Division of Clinical and Molecular Genetics, Henry Ford Hospital, Detroit, Michigan, 48202, USA

    C.E. Jackson

  9. Department of Anatomy and Cell Biology, The University of Toronto, Toronto, Ontario, M5S1A8, Canada

    L. Attisano

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Johnson, D., Berg, J., Baldwin, M. et al. Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13, 189–195 (1996). https://doi.org/10.1038/ng0696-189

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  • DOI: https://doi.org/10.1038/ng0696-189

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