Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Clinical and Molecular Genetic Features of Hereditary Pulmonary Arterial Hypertension

Laura Brenner, Wendy K. Chung

10.1002/cphy.c100063

Source: Volume 1, Issue 4, October 2011

Published online: October 2011

Full Article on Wiley Online Library



Abstract

Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditary (HPAH), idiopathic (IPAH), or associated with either drug‐toxin exposures or other medical conditions. Familial cases have long been recognised and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2), or, much less commonly, two other members of the transforming growth factor‐β superfamily, activin‐like kinase‐type 1 (ALK1), and endoglin (ENG), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counselling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome‐wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance, and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention. © 2011 American Physiological Society. Compr Physiol 1:1721‐1728, 2011.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Upon binding ligand, the type 2 receptor phosphorylates a type 1 partner, which may be BMPR1A/B or ALK1. This leads to a propagation of cytoplasmic signal transduction through the Smads 1/5/8, or, independently, via the p38 MAPKs (mitogen‐activated protein kinases). In association with Smad4, the Smads translocate to the nucleus and, in complex with transcriptional cofactors, modulate the expression of genes.


Figure 1.

Upon binding ligand, the type 2 receptor phosphorylates a type 1 partner, which may be BMPR1A/B or ALK1. This leads to a propagation of cytoplasmic signal transduction through the Smads 1/5/8, or, independently, via the p38 MAPKs (mitogen‐activated protein kinases). In association with Smad4, the Smads translocate to the nucleus and, in complex with transcriptional cofactors, modulate the expression of genes.

References
 1. Abdalla SA, Cymerman U, Rushlow D, Chen N, Stoeber GP, Lemire EG, Letarte M. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat 25: 320‐321, 2005.
 2. Abraham WT, Raynolds MV, Badesch DB, Wynne KM, Groves BM, Roden RL, Robertson AD, Lowes BD, Zisman LS, Voelkel NF, Bristow MR, Perryman MB. Angiotensin‐converting enzyme DD genotype in patients with primary pulmonary hypertension: Increased frequency and association with preserved haemodynamics. J Renin Angiotensin Aldosterone Syst 4: 27‐30, 2003.
 3. Aldred MA, Comhair SA, Varella‐Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, Coldren CD. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 182: 1153‐1160, 2010.
 4. Aldred MA, Machado RD, James V, Morrell NW, Trembath RC. Characterization of the BMPR2 5′‐untranslated region and a novel mutation in pulmonary hypertension. Am J Respir Crit Care Med 176: 819‐824, 2007.
 5. Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez‐Sanchez MA, Martensson G, Galie N, Manes A, Corris P, Simonneau G, Humbert M, Morrell NW, Trembath RC. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 27: 212‐213, 2006.
 6. Amano S, Tatsumi K, Tanabe N, Kasahara Y, Kurosu K, Takiguchi Y, Kasuya Y, Kimura S, Kuriyama T. Polymorphism of the promoter region of prostacyclin synthase gene in chronic thromboembolic pulmonary hypertension. Respirology 9: 184‐189, 2004.
 7. Bando B, Armitage JM, Paradis IL, Keenan RJ, Hardesty RL, Konishi H, Komatsu K, Stein KL, Shah AN, Bahnson HT, Griffith BP. Indications for and results of single, bilateral, and heart‐lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 108: 1056‐1065, 1994.
 8. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J. Clinical efficacy of sitaxsentan, an endothelin‐A receptor antagonist, in patients with pulmonary arterial hypertension: Open‐label pilot study. Chest 121: 1860‐1868, 2002.
 9. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langkeben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 334: 296‐302, 1996.
 10. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin‐receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo‐controlled study. Lancet 358: 1119‐1123, 2001.
 11. Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, Humbert M. Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59: 446‐448, 2004.
 12. Cogan JD, Pauciulo MW, Batchman AP, Prince MA, Robbins IM, Hedges LK, Stanton KC, Wheeler LA, Phillips JA, 3rd, Loyd JE, Nichols WC. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 174: 590‐598, 2006.
 13. Cogan JD, Vnencak‐Jones CL, Phillips JA, 3rd, Lane KB, Wheeler LA, Robbins IM, Garrison G, Hedges LK, Loyd JE. Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med 7: 169‐174, 2005.
 14. Davies RJ, Morrell NW. Molecular mechanisms of pulmonary arterial hypertension: Role of mutations in the bone morphogenetic protein type II receptor. Chest 134: 1271‐1277, 2008.
 15. Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, Hodge SE, Morse JH, Knowles JA. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3‐cM region on chromosome 2q33. Am J Respir Crit Care Med 161: 1055‐1059, 2000.
 16. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor‐II gene. Am J Hum Genet 67: 737‐744, 2000.
 17. Dresdale DT, Michtom RJ, Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med 30: 195‐207, 1954.
 18. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108: 1141‐1150, 2001.
 19. Elliott CG, Glissmeyer EW, Havlena GT, Carlquist J, McKinney JT, Rich S, McGoon MD, Scholand MB, Kim M, Jensen RL, Schmidt JW, Ward K. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 113: 2509‐2515, 2006.
 20. Fujiwara M, Yagi H, Matsuoka R, Akimoto K, Furutani M, Imamura S, Uehara R, Nakayama T, Takao A, Nakazawa M, Saji T. Implications of mutations of activin receptor‐like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J 72: 127‐133, 2008.
 21. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353: 2148‐2157, 2005.
 22. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 353: 1412‐1413, 2005.
 23. Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X, Tregouet D, Reis A, Drouin‐Garraud V, Fraisse A, Sitbon O, O'Callaghan DS, Simonneau G, Soubrier F, Humbert M. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 181: 851‐861, 2010.
 24. Greenwald J, Fischer WH, Vale WW, Choe S. Three‐finger toxin fold for the extracellular ligand‐binding domain of the type II activin receptor serine kinase. Nat Struct Biol 6: 18‐22, 1999.
 25. Grunig E, Mereles D, Arnold K, Benz A, Olschewski H, Miltenberger‐Miltenyi G, Borst MM, Abushi A, Seeger W, Winkler J, Hoper MM, Bartram CR, Kubler W, Janssen B. Primary pulmonary hypertension is predominantly a hereditary disease. Chest 121: 81S‐82S, 2002.
 26. Harper JC, Boelaert K, Geraedts J, Harton G, Kearns WG, Moutou C, Muntjewerff N, Repping S, SenGupta S, Scriven PN, Traeger‐Synodinos J, Vesela K, Wilton L, Sermon KD. ESHRE PGD Consortium data collection V: Cycles from January to December 2002 with pregnancy follow‐up to October 2003. Hum Reprod 21: 3‐21, 2006.
 27. Harrison RE, Berger R, Haworth SG, Tulloh R, Mache CJ, Morrell NW, Aldred MA, Trembath RC. Transforming growth factor‐beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation 111: 435‐441, 2005.
 28. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Halme M, Raisanen‐Sokolowski A, Laitinen T, Morrell NW, Trembath RC. Molecular and functional analysis identifies ALK‐1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 40: 865‐871, 2003.
 29. Hattersley AT, McCarthy MI. What makes a good genetic association study? Lancet 366: 1315‐1323, 2005.
 30. Higenbottam T, Wheeldon D, Wells F, Wallwork J. Long‐term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1: 1046‐1047, 1984.
 31. Hoeper MM, Tacacs A, Stellmacher U, Lichtinghagen R. Lack of association between angiotensin converting enzyme (ACE) genotype, serum ACE activity, and haemodynamics in patients with primary pulmonary hypertension. Heart 89: 445‐446, 2003.
 32. Humbert M, Deng Z, Simonneau G, Barst RJ, Sitbon O, Wolf M, Cuervo N, Moore KJ, Hodge SE, Knowles JA, Morse JH. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J 20: 518‐523, 2002.
 33. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud‐Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G. Pulmonary arterial hypertension in France: Results from a national registry. Am J Respir Crit Care Med 173: 1023‐1030, 2006.
 34. Jones DL, Sandberg JC, Rosenthal MJ, Saunders RC, Hannig VL, Clayton EW. What patients and their relatives think about testing for BMPR2. J Genet Couns 17: 452‐458, 2008.
 35. Koehler R, Olschewski H, Hoeper M, Janssen B, Grunig E. Serotonin transporter gene polymorphism in a cohort of German patients with idiopathic pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Chest 128: 619S, 2005.
 36. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, 3rd, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF‐beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26: 81‐84, 2000.
 37. Loyd JE, Atkinson JB, Pietra GG, Virmani R, Newman JH. Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 138: 952‐957, 1988.
 38. Loyd JE, Butler MG, Foroud TM, Conneally PM, Phillips JA, 3rd, Newman JH. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 152: 93‐97, 1995.
 39. Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, Elliott CG, Glissmeyer E, Carlquist J, Kim M, Torbicki A, Fijalkowska A, Szewczyk G, Parma J, Abramowicz MJ, Galie N, Morisaki H, Kyotani S, Nakanishi N, Morisaki T, Humbert M, Simonneau G, Sitbon O, Soubrier F, Coulet F, Morrell NW, Trembath RC. Mutations of the TGF‐beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27: 121‐132, 2006.
 40. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA, 3rd, Soubrier F, Trembath RC, Chung WK. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54: S32‐42, 2009.
 41. Machado RD, Koehler R, Glissmeyer E, Veal C, Suntharalingam J, Kim M, Carlquist J, Town M, Elliott CG, Hoeper M, Fijalkowska A, Kurzyna M, Thomson JR, Gibbs SR, Wilkins MR, Seeger W, Morrell NW, Gruenig E, Trembath RC, Janssen B. Genetic association of the serotonin transporter in pulmonary arterial hypertension. Am J Respir Crit Care Med 173: 793‐797, 2006.
 42. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA, 3rd, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 68: 92‐102, 2001.
 43. Mache CJ, Gamillscheg A, Popper HH, Haworth SG. Early‐life pulmonary arterial hypertension with subsequent development of diffuse pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia type 1. Thorax 63: 85‐86, 2008.
 44. McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, Loyd JE. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence‐based clinical practice guidelines. Chest 126: 14S‐34S, 2004.
 45. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 53: 1573‐1619, 2009.
 46. Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31‐q32. Circulation 95: 2603‐2606, 1997.
 47. Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, Coccolo F, Ventura C, Phillips JA, 3rd, Knowles JA, Janssen B, Eickelberg O, Eddahibi S, Herve P, Nichols WC, Elliott G. Genetic basis of pulmonary arterial hypertension: Current understanding and future directions. J Am Coll Cardiol 43: 33S‐39S, 2004.
 48. Nichols WC, Koller DL, Slovis B, Foroud T, Terry VH, Arnold ND, Siemieniak DR, Wheeler L, Phillips JA, 3rd, Newman JH, Conneally PM, Ginsburg D, Loyd JE. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31‐32. Nat Genet 15: 277‐280, 1997.
 49. Nishihara A, Watabe T, Imamura T, Miyazono K. Functional heterogeneity of bone morphogenetic protein receptor‐II mutants found in patients with primary pulmonary hypertension. Mol Biol Cell 13: 3055‐3063, 2002.
 50. Nunes H, Humbert M, Sitbon O, Morse JH, Deng Z, Knowles JA, Le Gall C, Parent F, Garcia G, Herve P, Barst RJ, Simonneau G. Prognostic factors for survival in human immunodeficiency virus‐associated pulmonary arterial hypertension. Am J Respir Crit Care Med 167: 1433‐1439, 2003.
 51. Phillips JA, 3rd, Poling JS, Phillips CA, Stanton KC, Austin ED, Cogan JD, Wheeler L, Yu C, Newman JH, Dietz HC, Loyd JE. Synergistic heterozygosity for TGFbeta1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genet Med 10: 359‐365, 2008.
 52. Prigoda NL, Savas S, Abdalla SA, Piovesan B, Rushlow D, Vandezande K, Zhang E, Ozcelik H, Gallie BL, Letarte M. Hereditary haemorrhagic telangiectasia: Mutation detection, test sensitivity and novel mutations. J Med Genet 43: 722‐728, 2006.
 53. Remillard CV, Tigno DD, Platoshyn O, Burg ED, Brevnova EE, Conger D, Nicholson A, Rana BK, Channick RN, Rubin LJ, O'Connor D T, Yuan JX. Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 292: C1837‐1853, 2007.
 54. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, Levy PC, Reid LM, Vreim CE, Williams GW. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 107: 216‐223, 1987.
 55. Roberts KE, McElroy JJ, Wong WP, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 24: 371‐374, 2004.
 56. Rosenzweig EB, Morse JH, Knowles JA, Chada KK, Khan AM, Roberts KE, McElroy JJ, Juskiw NK, Mallory NC, Rich S, Diamond B, Barst RJ. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant 27: 668‐674, 2008.
 57. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 336: 111‐117, 1997.
 58. Rudarakanchana N, Flanagan JA, Chen H, Upton PD, Machado R, Patel D, Trembath RC, Morrell NW. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 11: 1517‐1525, 2002.
 59. Shi Y, Massague J. Mechanisms of TGF‐beta signaling from cell membrane to the nucleus. Cell 113: 685‐700, 2003.
 60. Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 46: 331‐337, 2009.
 61. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43: 5S‐12S, 2004.
 62. Souza R, Humbert M, Sztrymf B, Jais X, Yaici A, Le Pavec J, Parent F, Herve P, Soubrier F, Sitbon O, Simonneau G. Pulmonary arterial hypertension associated with fenfluramine exposure: Report of 109 cases. Eur Respir J 31: 343‐348, 2008.
 63. Sztrymf B, Coulet F, Girerd B, Yaici A, Jais X, Sitbon O, Montani D, Souza R, Simonneau G, Soubrier F, Humbert M. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 177: 1377‐1383, 2008.
 64. Sztrymf B, Yaici A, Girerd B, Humbert M. Genes and pulmonary arterial hypertension. Respiration 74: 123‐132, 2007.
 65. Tew MB, Arnett FC, Reveille JD, Tan FK. Mutations of bone morphogenetic protein receptor type II are not found in patients with pulmonary hypertension and underlying connective tissue diseases. Arthritis Rheum 46: 2829‐2830, 2002.
 66. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC. 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 37: 741‐745, 2000.
 67. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345: 325‐334, 2001.
 68. Willers ED, Newman JH, Loyd JE, Robbins IM, Wheeler LA, Prince MA, Stanton KC, Cogan JA, Runo JR, Byrne D, Humbert M, Simonneau G, Sztrymf B, Morse JA, Knowles JA, Roberts KE, McElroy JJ, Barst RJ, Phillips JA, 3rd. Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 173: 798‐802, 2006.
 69. Wipff J, Kahan A, Hachulla E, Sibilia J, Cabane J, Meyer O, Mouthon L, Guillevin L, Junien C, Boileau C, Allanore Y. Association between an endoglin gene polymorphism and systemic sclerosis‐related pulmonary arterial hypertension. Rheumatology (Oxford) 46: 622‐625, 2007.

Related Articles:

Pulmonary Vascular Disease

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Clinical and Molecular Genetic Features of Hereditary Pulmonary Arterial Hypertension
 

How to Cite

Laura Brenner, Wendy K. Chung. Clinical and Molecular Genetic Features of Hereditary Pulmonary Arterial Hypertension. Compr Physiol 2011, 1: 1721-1728. doi: 10.1002/cphy.c100063