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. 2003 Dec;40(12):865–871. doi: 10.1136/jmg.40.12.865

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia

R Harrison 1, J Flanagan 1, M Sankelo 1, S Abdalla 1, J Rowell 1, R Machado 1, C Elliott 1, I Robbins 1, H Olschewski 1, V McLaughlin 1, E Gruenig 1, F Kermeen 1, T Laitinen 1, N Morrell 1, R Trembath 1
PMCID: PMC1735342  PMID: 14684682

Abstract

Background: Mutations of the transforming growth factor ß (TGFß) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension.

Objective: To investigate kindreds presenting with both pulmonary hypertension and HHT.

Methods: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling.

Results: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN.

Conclusions: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

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Selected References

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  1. Abdalla S. A., Geisthoff U. W., Bonneau D., Plauchu H., McDonald J., Kennedy S., Faughnan M. E., Letarte M. Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. J Med Genet. 2003 Jul;40(7):494–502. doi: 10.1136/jmg.40.7.494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Abdalla Salma A., Cymerman Urszula, Johnson Rachel M., Deber Charles M., Letarte Michelle. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003 Apr;11(4):279–287. doi: 10.1038/sj.ejhg.5200919. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. 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]
  7. De Angelis Elena, Watkins Alex, Schäfer Michael, Brümmendorf Thomas, Kenwrick Sue. Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. Hum Mol Genet. 2002 Jan 1;11(1):1–12. doi: 10.1093/hmg/11.1.1. [DOI] [PubMed] [Google Scholar]
  8. Deng Z., Morse J. H., Slager S. L., Cuervo N., Moore K. J., Venetos G., Kalachikov S., Cayanis E., Fischer S. G., Barst R. J. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000 Jul 20;67(3):737–744. doi: 10.1086/303059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Garamszegi N., Doré J. J., Jr, Penheiter S. G., Edens M., Yao D., Leof E. B. Transforming growth factor beta receptor signaling and endocytosis are linked through a COOH terminal activation motif in the type I receptor. Mol Biol Cell. 2001 Sep;12(9):2881–2893. doi: 10.1091/mbc.12.9.2881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Humbert M., Deng Z., Simonneau G., Barst R. J., Sitbon O., Wolf M., Cuervo N., Moore K. J., Hodge S. E., Knowles J. A. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. 2002 Sep;20(3):518–523. doi: 10.1183/09031936.02.01762002. [DOI] [PubMed] [Google Scholar]
  11. Huse M., Chen Y. G., Massagué J., Kuriyan J. Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12. Cell. 1999 Feb 5;96(3):425–436. doi: 10.1016/s0092-8674(00)80555-3. [DOI] [PubMed] [Google Scholar]
  12. Huse M., Muir T. W., Xu L., Chen Y. G., Kuriyan J., Massagué J. The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell. 2001 Sep;8(3):671–682. doi: 10.1016/s1097-2765(01)00332-x. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Klaus D. J., Gallione C. J., Anthony K., Yeh E. Y., Yu J., Lux A., Johnson D. W., Marchuk D. A. Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online. Hum Mutat. 1998;12(2):137–137. doi: 10.1002/(SICI)1098-1004(1998)12:2<137::AID-HUMU16>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  16. Lehmann Katarina, Seemann Petra, Stricker Sigmar, Sammar Marai, Meyer Birgit, Süring Katrin, Majewski Frank, Tinschert Sigrid, Grzeschik Karl-Heinz, Müller Dietmar. Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proc Natl Acad Sci U S A. 2003 Oct 1;100(21):12277–12282. doi: 10.1073/pnas.2133476100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lin W. D., Wu J. Y., Hsu H. B., Tsai F. J., Lee C. C., Tsai C. H. Mutation analysis of a family with hereditary hemorrhagic telangiectasia associated with hepatic arteriovenous malformation. J Formos Med Assoc. 2001 Dec;100(12):817–819. [PubMed] [Google Scholar]
  18. Loyd J. E., Primm R. K., Newman J. H. Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis. 1984 Jan;129(1):194–197. doi: 10.1164/arrd.1984.129.1.194. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. Olivieri C., Mira E., Delù G., Pagella F., Zambelli A., Malvezzi L., Buscarini E., Danesino C. Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. J Med Genet. 2002 Jul;39(7):E39–E39. doi: 10.1136/jmg.39.7.e39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Sapru R. P., Hutchison D. C., Hall J. I. Pulmonary hypertension in patients with pulmonary arteriovenous fistulae. Br Heart J. 1969 Sep;31(5):559–569. doi: 10.1136/hrt.31.5.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shi Yigong, Massagué Joan. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003 Jun 13;113(6):685–700. doi: 10.1016/s0092-8674(03)00432-x. [DOI] [PubMed] [Google Scholar]
  25. Shovlin C. L., Guttmacher A. E., Buscarini E., Faughnan M. E., Hyland R. H., Westermann C. J., Kjeldsen A. D., Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000 Mar 6;91(1):66–67. doi: 10.1002/(sici)1096-8628(20000306)91:1<66::aid-ajmg12>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  26. Thomas A. Q., Gaddipati R., Newman J. H., Loyd J. E. Genetics of primary pulmonary hypertension. Clin Chest Med. 2001 Sep;22(3):477-91, ix. doi: 10.1016/s0272-5231(05)70285-9. [DOI] [PubMed] [Google Scholar]
  27. Thomson J. R., Machado R. D., Pauciulo M. W., Morgan N. V., Humbert M., Elliott G. C., Ward K., Yacoub M., Mikhail G., Rogers P. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000 Oct;37(10):741–745. doi: 10.1136/jmg.37.10.741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Trembath R. C., Thomson J. R., Machado R. D., Morgan N. V., Atkinson C., Winship I., Simonneau G., Galie N., Loyd J. E., Humbert M. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001 Aug 2;345(5):325–334. doi: 10.1056/NEJM200108023450503. [DOI] [PubMed] [Google Scholar]
  29. van den Driesche Sander, Mummery Christine L., Westermann Cornelius J. J. Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis. Cardiovasc Res. 2003 Apr 1;58(1):20–31. doi: 10.1016/s0008-6363(02)00852-0. [DOI] [PubMed] [Google Scholar]

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