Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 345 (5), 325-34

Clinical and Molecular Genetic Features of Pulmonary Hypertension in Patients With Hereditary Hemorrhagic Telangiectasia

Affiliations

Clinical and Molecular Genetic Features of Pulmonary Hypertension in Patients With Hereditary Hemorrhagic Telangiectasia

R C Trembath et al. N Engl J Med.

Abstract

Background: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients.

Methods: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations.

Results: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries.

Conclusions: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.

Comment in

Similar articles

See all similar articles

Cited by 140 articles

  • Joint Transcriptomic Analysis of Lung Cancer and Other Lung Diseases.
    Otálora-Otálora BA, Florez M, López-Kleine L, Canas Arboleda A, Grajales Urrego DM, Rojas A. Otálora-Otálora BA, et al. Front Genet. 2019 Dec 6;10:1260. doi: 10.3389/fgene.2019.01260. eCollection 2019. Front Genet. 2019. PMID: 31867044 Free PMC article.
  • Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.
    Hodgson J, Swietlik EM, Salmon RM, Hadinnapola C, Nikolic I, Wharton J, Guo J, Liley J, Haimel M, Bleda M, Southgate L, Machado RD, Martin JM, Treacy CM, Yates K, Daugherty LC, Shamardina O, Whitehorn D, Holden S, Bogaard HJ, Church C, Coghlan G, Condliffe R, Corris PA, Danesino C, Eyries M, Gall H, Ghio S, Ghofrani HA, Gibbs JSR, Girerd B, Houweling AC, Howard L, Humbert M, Kiely DG, Kovacs G, Lawrie A, MacKenzie Ross RV, Moledina S, Montani D, Olschewski A, Olschewski H, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Prokopenko I, Rhodes CJ, Scelsi L, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Trembath RC, Noordegraaf AV, Wort SJ, Wilkins MR, Yu PB, Li W, Gräf S, Upton PD, Morrell NW. Hodgson J, et al. Am J Respir Crit Care Med. 2020 Mar 1;201(5):575-585. doi: 10.1164/rccm.201906-1141OC. Am J Respir Crit Care Med. 2020. PMID: 31661308
  • Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an ACVRL1 Mutation.
    Yokokawa T, Sugimoto K, Kimishima Y, Misaka T, Yoshihisa A, Morisaki H, Yamada O, Nakazato K, Ishida T, Takeishi Y. Yokokawa T, et al. Intern Med. 2020 Jan 15;59(2):221-227. doi: 10.2169/internalmedicine.3625-19. Epub 2019 Sep 11. Intern Med. 2020. PMID: 31511490 Free PMC article.
  • Variant analysis in Chinese families with hereditary hemorrhagic telangiectasia.
    Zhao Y, Zhang Y, Wang X, Zhang L. Zhao Y, et al. Mol Genet Genomic Med. 2019 Sep;7(9):e893. doi: 10.1002/mgg3.893. Epub 2019 Aug 10. Mol Genet Genomic Med. 2019. PMID: 31400083 Free PMC article.
  • United States Pulmonary Hypertension Scientific Registry (USPHSR): rationale, design, and clinical implications.
    Elliott CG, Austin ED, Badesch D, Badlam J, Benza RL, Chung WK, Farber HW, Feldkircher K, Frost AE, Poms AD, Lutz KA, Pauciulo MW, Yu C, Nichols WC. Elliott CG, et al. Pulm Circ. 2019 Apr-Jun;9(2):2045894019851696. doi: 10.1177/2045894019851696. Pulm Circ. 2019. PMID: 31099303 Free PMC article.
See all "Cited by" articles

Publication types

MeSH terms

Substances

Feedback