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. 2003 Aug;40(8):585–590. doi: 10.1136/jmg.40.8.585

Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations

J Berg 1, M Porteous 1, D Reinhardt 1, C Gallione 1, S Holloway 1, T Umasunthar 1, A Lux 1, W McKinnon 1, D Marchuk 1, A Guttmacher 1
PMCID: PMC1735540  PMID: 12920067

Abstract

Background: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterised by mucocutaneous telangiectasis, epistaxis, gastrointestinal haemorrhage, and arteriovenous malformations in the lung and brain. Causative mutations for HHT have been identified in two genes, endoglin and ALK1, which encode proteins involved in serine-threonine kinase signalling in the endothelial cell.

Methods: A number of people affected with HHT had completed a postal questionnaire as part of an international study to delineate the HHT phenotype. We identified questionnaires completed by subjects in whom we had identified a mutation in endoglin or ALK1. Further questionnaires were sent to families with known mutations. Data were only included from questionnaires returned by people known to carry disease causing mutations.

Results: Questionnaires were completed by 83 subjects with known mutations. Of these, 49 had endoglin mutations (HHT1) and 34 had ALK1 mutations (HHT2). Subjects with HHT1 reported an earlier onset of epistaxis (p=0.01) and telangiectasis (p=0.0001) than those with HHT2. Pulmonary arteriovenous malformations were only reported in the endoglin mutation group in our study (p<0.001).

Conclusions: Our questionnaire based study provides evidence that the HHT phenotype caused by mutations in endoglin (HHT1) is distinct from, and more severe than, HHT caused by mutations in ALK1 (HHT2). This has significant implications for diagnosis, screening, and treatment in the two different forms of HHT, as well as for understanding the pathogenesis of the disease.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abdalla S. A., Pece-Barbara N., Vera S., Tapia E., Paez E., Bernabeu C., Letarte M. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000 May 1;9(8):1227–1237. doi: 10.1093/hmg/9.8.1227. [DOI] [PubMed] [Google Scholar]
  2. Adam P. J., Clesham G. J., Weissberg P. L. Expression of endoglin mRNA and protein in human vascular smooth muscle cells. Biochem Biophys Res Commun. 1998 Jun 9;247(1):33–37. doi: 10.1006/bbrc.1998.8734. [DOI] [PubMed] [Google Scholar]
  3. Attisano L., Cárcamo J., Ventura F., Weis F. M., Massagué J., Wrana J. L. Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 1993 Nov 19;75(4):671–680. doi: 10.1016/0092-8674(93)90488-c. [DOI] [PubMed] [Google Scholar]
  4. Barbara N. P., Wrana J. L., Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem. 1999 Jan 8;274(2):584–594. doi: 10.1074/jbc.274.2.584. [DOI] [PubMed] [Google Scholar]
  5. Berg J. N., Gallione C. J., Stenzel T. T., Johnson D. W., Allen W. P., Schwartz C. E., Jackson C. E., Porteous M. E., Marchuk D. A. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60–67. doi: 10.1086/513903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berg J. N., Guttmacher A. E., Marchuk D. A., Porteous M. E. Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J Med Genet. 1996 Mar;33(3):256–257. doi: 10.1136/jmg.33.3.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bideau A., Plauchu H., Jacquard A., Robert J. M., Desjardins B. La génopathie de Rendu-Osler dans le Haut-Jura: convergences des approches méthodologiques de la démographie historique et de la génétique. J Genet Hum. 1980 Jun;28(2):127–147. [PubMed] [Google Scholar]
  8. Buscarini E., Buscarini L., Danesino C., Piantanida M., Civardi G., Quaretti P., Rossi S., Di Stasi M., Silva M. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family. J Hepatol. 1997 Jan;26(1):111–118. doi: 10.1016/s0168-8278(97)80017-7. [DOI] [PubMed] [Google Scholar]
  9. Caniggia I., Taylor C. V., Ritchie J. W., Lye S. J., Letarte M. Endoglin regulates trophoblast differentiation along the invasive pathway in human placental villous explants. Endocrinology. 1997 Nov;138(11):4977–4988. doi: 10.1210/endo.138.11.5475. [DOI] [PubMed] [Google Scholar]
  10. Cheifetz S., Bellón T., Calés C., Vera S., Bernabeu C., Massagué J., Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem. 1992 Sep 25;267(27):19027–19030. [PubMed] [Google Scholar]
  11. Chen Y. G., Massagué J. Smad1 recognition and activation by the ALK1 group of transforming growth factor-beta family receptors. J Biol Chem. 1999 Feb 5;274(6):3672–3677. doi: 10.1074/jbc.274.6.3672. [DOI] [PubMed] [Google Scholar]
  12. Conley B. A., Smith J. D., Guerrero-Esteo M., Bernabeu C., Vary C. P. Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. Atherosclerosis. 2000 Dec;153(2):323–335. doi: 10.1016/s0021-9150(00)00422-6. [DOI] [PubMed] [Google Scholar]
  13. Dutton J. A., Jackson J. E., Hughes J. M., Whyte M. K., Peters A. M., Ussov W., Allison D. J. Pulmonary arteriovenous malformations: results of treatment with coil embolization in 53 patients. AJR Am J Roentgenol. 1995 Nov;165(5):1119–1125. doi: 10.2214/ajr.165.5.7572487. [DOI] [PubMed] [Google Scholar]
  14. Gallione C. J., Klaus D. J., Yeh E. Y., Stenzel T. T., Xue Y., Anthony K. B., McAllister K. A., Baldwin M. A., Berg J. N., Lux A. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286–294. doi: 10.1002/(SICI)1098-1004(1998)11:4<286::AID-HUMU6>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  15. Garcia-Tsao G., Korzenik J. R., Young L., Henderson K. J., Jain D., Byrd B., Pollak J. S., White R. I., Jr Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2000 Sep 28;343(13):931–936. doi: 10.1056/NEJM200009283431305. [DOI] [PubMed] [Google Scholar]
  16. Gougos A., Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem. 1990 May 25;265(15):8361–8364. [PubMed] [Google Scholar]
  17. Guerrero-Esteo M., Lastres P., Letamendía A., Pérez-Alvarez M. J., Langa C., López L. A., Fabra A., García-Pardo A., Vera S., Letarte M. Endoglin overexpression modulates cellular morphology, migration, and adhesion of mouse fibroblasts. Eur J Cell Biol. 1999 Sep;78(9):614–623. doi: 10.1016/S0171-9335(99)80046-6. [DOI] [PubMed] [Google Scholar]
  18. Guerrero-Esteo Mercedes, Sanchez-Elsner Tilman, Letamendia Ainhoa, Bernabeu Carmelo. Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II. J Biol Chem. 2002 May 15;277(32):29197–29209. doi: 10.1074/jbc.M111991200. [DOI] [PubMed] [Google Scholar]
  19. Guttmacher A. E., Marchuk D. A., White R. I., Jr Hereditary hemorrhagic telangiectasia. N Engl J Med. 1995 Oct 5;333(14):918–924. doi: 10.1056/NEJM199510053331407. [DOI] [PubMed] [Google Scholar]
  20. Guttmacher A. E., McKinnon W. C., Upton M. D. Hereditary hemorrhagic telangiectasia: a disorder in search of the genetics community. Am J Med Genet. 1994 Aug 15;52(2):252–253. doi: 10.1002/ajmg.1320520232. [DOI] [PubMed] [Google Scholar]
  21. Johnson D. W., Berg J. N., Baldwin M. A., Gallione C. J., Marondel I., Yoon S. J., Stenzel T. T., Speer M., Pericak-Vance M. A., Diamond A. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996 Jun;13(2):189–195. doi: 10.1038/ng0696-189. [DOI] [PubMed] [Google Scholar]
  22. Kjeldsen A. D., Brusgaard K., Poulsen L., Kruse T., Rasmussen K., Green A., Vase P. Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families. Am J Med Genet. 2001 Feb 1;98(4):298–302. doi: 10.1002/1096-8628(20010201)98:4<298::aid-ajmg1093>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  23. Kjeldsen A. D., Kjeldsen J. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol. 2000 Feb;95(2):415–418. doi: 10.1111/j.1572-0241.2000.01792.x. [DOI] [PubMed] [Google Scholar]
  24. Lastres P., Bellon T., Cabañas C., Sanchez-Madrid F., Acevedo A., Gougos A., Letarte M., Bernabeu C. Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-containing surface antigen. Eur J Immunol. 1992 Feb;22(2):393–397. doi: 10.1002/eji.1830220216. [DOI] [PubMed] [Google Scholar]
  25. Leask A., Abraham D. J., Finlay D. R., Holmes A., Pennington D., Shi-Wen X., Chen Y., Venstrom K., Dou X., Ponticos M. Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum. 2002 Jul;46(7):1857–1865. doi: 10.1002/art.10333. [DOI] [PubMed] [Google Scholar]
  26. Li C., Hampson I. N., Hampson L., Kumar P., Bernabeu C., Kumar S. CD105 antagonizes the inhibitory signaling of transforming growth factor beta1 on human vascular endothelial cells. FASEB J. 2000 Jan;14(1):55–64. doi: 10.1096/fasebj.14.1.55. [DOI] [PubMed] [Google Scholar]
  27. Lux A., Attisano L., Marchuk D. A. Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. J Biol Chem. 1999 Apr 9;274(15):9984–9992. doi: 10.1074/jbc.274.15.9984. [DOI] [PubMed] [Google Scholar]
  28. Ma X., Labinaz M., Goldstein J., Miller H., Keon W. J., Letarte M., O'Brien E. Endoglin is overexpressed after arterial injury and is required for transforming growth factor-beta-induced inhibition of smooth muscle cell migration. Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):2546–2552. doi: 10.1161/01.atv.20.12.2546. [DOI] [PubMed] [Google Scholar]
  29. Macías-Silva M., Hoodless P. A., Tang S. J., Buchwald M., Wrana J. L. Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem. 1998 Oct 2;273(40):25628–25636. doi: 10.1074/jbc.273.40.25628. [DOI] [PubMed] [Google Scholar]
  30. Maher C. O., Piepgras D. G., Brown R. D., Jr, Friedman J. A., Pollock B. E. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke. 2001 Apr;32(4):877–882. doi: 10.1161/01.str.32.4.877. [DOI] [PubMed] [Google Scholar]
  31. McAllister K. A., Baldwin M. A., Thukkani A. K., Gallione C. J., Berg J. N., Porteous M. E., Guttmacher A. E., Marchuk D. A. Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type 1 suggest a dominant-negative effect of receptor function. Hum Mol Genet. 1995 Oct;4(10):1983–1985. doi: 10.1093/hmg/4.10.1983. [DOI] [PubMed] [Google Scholar]
  32. McAllister K. A., Grogg K. M., Johnson D. W., Gallione C. J., Baldwin M. A., Jackson C. E., Helmbold E. A., Markel D. S., McKinnon W. C., Murrell J. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994 Dec;8(4):345–351. doi: 10.1038/ng1294-345. [DOI] [PubMed] [Google Scholar]
  33. McDonald J. E., Miller F. J., Hallam S. E., Nelson L., Marchuk D. A., Ward K. J. Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. Am J Med Genet. 2000 Aug 14;93(4):320–327. doi: 10.1002/1096-8628(20000814)93:4<320::aid-ajmg12>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  34. Plauchu H., de Chadarévian J. P., Bideau A., Robert J. M. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989 Mar;32(3):291–297. doi: 10.1002/ajmg.1320320302. [DOI] [PubMed] [Google Scholar]
  35. Porteous M. E., Burn J., Proctor S. J. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992 Aug;29(8):527–530. doi: 10.1136/jmg.29.8.527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shovlin C. L., Winstock A. R., Peters A. M., Jackson J. E., Hughes J. M. Medical complications of pregnancy in hereditary haemorrhagic telangiectasia. QJM. 1995 Dec;88(12):879–887. [PubMed] [Google Scholar]
  37. Steele J. G., Nath P. U., Burn J., Porteous M. E. An association between migrainous aura and hereditary haemorrhagic telangiectasia. Headache. 1993 Mar;33(3):145–148. doi: 10.1111/j.1526-4610.1993.hed3303145.x. [DOI] [PubMed] [Google Scholar]
  38. Vase P., Holm M., Arendrup H. Pulmonary arteriovenous fistulas in hereditary hemorrhagic telangiectasia. Acta Med Scand. 1985;218(1):105–109. doi: 10.1111/j.0954-6820.1985.tb08832.x. [DOI] [PubMed] [Google Scholar]
  39. Zwijsen A., van Grunsven L. A., Bosman E. A., Collart C., Nelles L., Umans L., Van de Putte T., Wuytens G., Huylebroeck D., Verschueren K. Transforming growth factor beta signalling in vitro and in vivo: activin ligand-receptor interaction, Smad5 in vasculogenesis, and repression of target genes by the deltaEF1/ZEB-related SIP1 in the vertebrate embryo. Mol Cell Endocrinol. 2001 Jun 30;180(1-2):13–24. doi: 10.1016/s0303-7207(01)00505-6. [DOI] [PubMed] [Google Scholar]
  40. ten Dijke P., Ichijo H., Franzén P., Schulz P., Saras J., Toyoshima H., Heldin C. H., Miyazono K. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene. 1993 Oct;8(10):2879–2887. [PubMed] [Google Scholar]

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