Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects

Human Mutation

Volumn 36, Issue 12, 2015, Pages 1113-1127

  Machado, Rajiv D ^a   Southgate, Laura ^b,c   Eichstaedt, Christina A ^d,e   Aldred, Micheala A ^f   Austin, Eric D ^g   Best, D Hunter ^h,i   Chung, Wendy K ^j   Benjamin, Nicola ^d   Elliott, C Gregory ^h   Eyries, Mélanie ^k,l,m   Fischer, Christine ^e   Gräf, Stefan ^n,o   Hinderhofer, Katrin ^e   Humbert, Marc ^p,q,r   Keiles, Steven B ^s   Loyd, James E ^t   Morrell, Nicholas W ^n,u   Newman, John H ^t   Soubrier, Florent ^k,l,m   Trembath, Richard C ^b   Viales, Rebecca Rodríguez ^d,e   Grünig, Ekkehard ^d   more..

^a UNIVERSITY OF LINCOLN   (United Kingdom)

^b QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^c KING'S COLLEGE LONDON   (United Kingdom)

^d UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^e UNIVERSITY OF HEIDELBERG   (Germany)

^f LERNER RESEARCH INSTITUTE   (United States)

^g VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^h UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

ⁱ ARUP INSTITUTE FOR CLINICAL AND EXPERIMENTAL PATHOLOGY   (United States)

^j NewYork Presbyterian Hospital   (United States)

^k Institute OfCardiometabolism and Nutrition   (France)

^l ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS   (France)

^m ICAN Institute for Cardiometabolism and Nutrition   (France)

ⁿ UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^o UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^p UNIVERSITÉ PARIS SACLAY   (France)

^q BICÊTRE HOSPITAL   (France)

^r CENTRE CHIRURGICAL MARIE LANNELONGUE   (France)

^s QUEST DIAGNOSTICS NICHOLS INSTITUTE   (United States)

^t VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^u ADDENBROOKE S HOSPITAL   (United Kingdom)

more..

Author keywords

ACVRL1; BMPR2; CAV1; EIF2AK4; ENG; Haploinsufficiency; KCNA5; KCNK3; Locus heterogeneity; SMAD1; SMAD4; SMAD9

Indexed keywords

ACTIVIN RECEPTOR LIKE KINASE 1; BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CAVEOLIN 1; ENDOGLIN; EUKARYOTIC TRANSLATION INITIATION FACTOR 2 ALPHA KINASE 4; POTASSIUM CHANNEL; POTASSIUM CHANNEL KCNK3; POTASSIUM CHANNEL KV1.5; PROTEIN SERINE THREONINE KINASE; SMAD PROTEIN; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG;

ALLELE; DISEASE PREDISPOSITION; EXON; GENE LOCUS; GENE MUTATION; GENETIC COUNSELING; GENETIC RISK; GENETIC VARIABILITY; HUMAN; LUNG BLOOD VESSEL; MOLECULAR GENETICS; NEXT GENERATION SEQUENCING; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REVIEW; ANIMAL; CHEMISTRY; DISEASE MODEL; GENETIC ASSOCIATION STUDY; GENETIC PREDISPOSITION; GENETIC VARIATION; GENETICS; HIGH THROUGHPUT SEQUENCING; HYPERTENSION, PULMONARY; METABOLISM; MULTIGENE FAMILY; MUTATION; SIGNAL TRANSDUCTION;

ANIMALS; BONE MORPHOGENETIC PROTEIN RECEPTORS, TYPE II; DISEASE MODELS, ANIMAL; GENETIC ASSOCIATION STUDIES; GENETIC COUNSELING; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; HYPERTENSION, PULMONARY; MULTIGENE FAMILY; MUTATION; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA;

EID: 84946576433     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22904     Document Type: Review

References (101)

1. Abdalla SA, Gallione CJ, Barst RJ, Horn EM, Knowles JA, Marchuk DA, Letarte M, Morse JH. 2004. Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J 23:373-377.
2. Adzhubei I, Jordan DM, Sunyaev SR. 2013. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet: Chapter 7:Unit7.20.
3. Aldred MA, Machado RD, James V, Morrell NW, Trembath RC. 2007. Characterization of the BMPR2 5′-untranslated region and a novel mutation in pulmonary hypertension. Am J Respir Crit Care Med 176:819-824.
4. 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, et al. 2006. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 27:212-213.
5. Archer SL, Weir EK, Wilkins MR. 2010. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 121:2045-2066.
6. Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA 3rd. 2009a. Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J 34:1093-1099.
7. Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA 3rd, Palomero T, Sumazin P, Kim HR, Talati MH, West J, Loyd JE, et al. 2012. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 5:336-343.
8. Austin ED, Phillips JA, Cogan JD, Hamid R, Yu C, Stanton KC, Phillips CA, Wheeler LA, Robbins IM, Newman JH, Loyd JE. 2009b. Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respir Res 10:87.
9. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. 2007. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 131:1917-1928.
10. Best DH, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, Rosenzweig EB, Bayrak-Toydemir P, Mao R, Cahill BC, Tazelaar HD, Leslie KO, et al. 2014. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest 145:231-236.
11. Best DH, Vaughn C, McDonald J, Damjanovich K, Runo JR, Chibuk JM, Bayrak-Toydemir P. 2011. Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. J Med Genet 48:358-360.
12. Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, Humbert M. 2004. Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59:446-448.
13. Chen YJ, Yang QH, Liu D, Liu QQ, Eyries M, Wen L, Wu WH, Jiang X, Yuan P, Zhang R, Soubrier F, Jing ZC. 2013. Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension. Eur J Clin Invest 43:1016-1024.
14. Chida A, Shintani M, Nakayama T, Furutani Y, Hayama E, Inai K, Saji T, Nonoyama S, Nakanishi T. 2012a. Missense mutations of the BMPR1B (ALK6) gene in childhood idiopathic pulmonary arterial hypertension. Circ J 76:1501-1508.
15. Chida A, Shintani M, Yagi H, Fujiwara M, Kojima Y, Sato H, Imamura S, Yokozawa M, Onodera N, Horigome H, Kobayashi T, Hatai Y, et al. 2012b. Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. Am J Cardiol 110:586-593.
16. Chidlow JH Jr, Sessa WC. 2010. Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc Res 86:219-225.
17. Choi Y, Chan AP. 2015. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31:2745-2747.
18. Cogan JD, Pauciulo MW, Batchman AP, Prince MA, Robbins IM, Hedges LK, Stanton KC, Wheeler LA, Phillips JA 3rd, Loyd JE, Nichols WC. 2006. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 174:590-598.
19. Cogan J, Austin E, Hedges L, Womack B, West J, Loyd J, Hamid R. 2012. Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. Circulation 126:1907-1916.
20. Dahal GR, Rawson J, Gassaway B, Kwok B, Tong Y, Ptacek LJ, Bates E. 2012. An inwardly rectifying K+ channel is required for patterning. Development 139:3653-3664.
21. David L, Feige JJ, Bailly S. 2009. Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev 20:203-212.
22. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. 2000. 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.
23. Donnelly N, Gorman AM, Gupta S, Samali A. 2013. The eIF2alpha kinases: their structures and functions. Cell Mol Life Sci 70:3493-3511.
24. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, et al. 2001. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449-2452.
25. Drake KM, Zygmunt D, Mavrakis L, Harbor P, Wang L, Comhair SA, Erzurum SC, Aldred MA. 2011. Altered microRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med 184:1400-1408.
26. Elliott CG, Glissmeyer EW, Havlena GT, Carlquist J, McKinney JT, Rich S, McGoon MD, Scholand MB, Kim M, Jensen RL, Schmidt JW, Ward K. 2006. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 113:2509-2515.
27. Eyries M, Coulet F, Girerd B, Montani D, Humbert M, Lacombe P, Chinet T, Gouya L, Roume J, Axford MM, Pearson CE, Soubrier F. 2012. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Clin Genet 82:173-179.
28. Eyries M, Montani D, Girerd B, Perret C, Leroy A, Lonjou C, Chelghoum N, Coulet F, Bonnet D, Dorfmuller P, Fadel E, Sitbon O, et al. 2014. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 46:65-69.
29. Feng YX, Liu D, Sun ML, Jiang X, Sun N, Mao YM, Jing ZC. 2014. BMPR2 germline mutation in chronic thromboembolic pulmonary hypertension. Lung 192:625-627.
30. Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massague J, Bernard O. 2003. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 162:1089-1098.
31. Frydman N, Steffann J, Girerd B, Frydman R, Munnich A, Simonneau G, Humbert M. 2012. Pre-implantation genetic diagnosis in pulmonary arterial hypertension due to BMPR2 mutation. Eur Respir J 39:1534-1535.
32. Fujiwara M, Yagi H, Matsuoka R, Akimoto K, Furutani M, Imamura S, Uehara R, Nakayama T, Takao A, Nakazawa M, Saji T. 2008. 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.
33. Germain M, Eyries M, Montani D, Poirier O, Girerd B, Dorfmuller P, Coulet F, Nadaud S, Maugenre S, Guignabert C, Carpentier W, Vonk-Noordegraaf A, et al. 2013. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 45:518-521.
34. Girerd B, Coulet F, Jais X, Eyries M, Van Der Bruggen C, De Man F, Houweling A, Dorfmuller P, Savale L, Sitbon O, Vonk-Noordegraaf A, Soubrier F, et al. 2015. Characteristics of pulmonary arterial hypertension in affected carriers of a mutation located in the cytoplasmic tail of bone morphogenetic protein receptor type 2. Chest 147:1385-1394.
35. 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, et al. 2010a. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 181:851-861.
36. Girerd B, Montani D, Eyries M, Yaici A, Sztrymf B, Coulet F, Sitbon O, Simonneau G, Soubrier F, Humbert M. 2010b. Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir Res 11:73.
37. Greenwald J, Fischer WH, Vale WW, Choe S. 1999. Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase. Nat Struct Biol 6:18-22.
38. Harrison RE, Berger R, Haworth SG, Tulloh R, Mache CJ, Morrell NW, Aldred MA, Trembath RC. 2005. Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation 111:435-441.
39. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, et al. 2003. 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.
40. Hinderhofer K, Fischer C, Pfarr N, Szamalek-Hoegel J, Lichtblau M, Nagel C, Egenlauf B, Ehlken N, Grünig E. 2014. Identification of a new intronic BMPR2-mutation and early diagnosis of heritable pulmonary arterial hypertension in a large family with mean clinical follow-up of 12 years. PLoS One 9:e91374.
41. Hong KH, Lee YJ, Lee E, Park SO, Han C, Beppu H, Li E, Raizada MK, Bloch KD, Oh SP. 2008. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 118:722-730.
42. Huang Z, Wang D, Ihida-Stansbury K, Jones PL, Martin JF. 2009. Defective pulmonary vascular remodeling in Smad8 mutant mice. Hum Mol Genet 18:2791-2801.
43. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, et al. 2010. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122:156-163.
44. Ishiwata T, Terada J, Tanabe N, Abe M, Sugiura T, Tsushima K, Tada Y, Sakao S, Kasahara Y, Nakanishi N, Morisaki H, Tatsumi K. 2014. Pulmonary arterial hypertension as the first manifestation in a patient with hereditary hemorrhagic telangiectasia. Intern Med 53:2359-2363.
45. Jones G, Robertson L, Harrison R, Ridout C, Vasudevan P. 2014. Somatic mosaicism in ACVRL1 with transmission to several offspring affected with severe pulmonary arterial hypertension. Am J Med Genet A 164A:2121-2123.
46. Kabata H, Satoh T, Kataoka M, Tamura Y, Ono T, Yamamoto M, Huqun, Hagiwara K, Fukuda K, Betsuyaku T, Asano K. 2013. Bone morphogenetic protein receptor type 2 mutations, clinical phenotypes and outcomes of Japanese patients with sporadic or familial pulmonary hypertension. Respirology 18:1076-1082.
47. Koehler R, Grünig E, Pauciulo MW, Hoeper MM, Olschewski H, Wilkens H, Halank M, Winkler J, Ewert R, Bremer H, Kreuscher S, Janssen B, et al. 2004. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. J Med Genet 41:e127.
48. Kumar P, Henikoff S, Ng PC. 2009. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073-1081.
49. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC. 2000. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81-84.
50. Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, West JD, Phillips JA 3rd, Hamid R, Loyd JE. 2012. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 186:892-896.
51. Liu D, Liu QQ, Eyries M, Wu WH, Yuan P, Zhang R, Soubrier F, Jing ZC. 2012. Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients. Eur Respir J 39:597-603.
52. Liu F, Ventura F, Doody J, Massague J. 1995. Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 15:3479-3486.
53. Long L, Ormiston ML, Yang X, Southwood M, Graf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore SD, Drake KM, et al. 2015. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 21:777-785.
54. Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Tregouet DA, Borczuk A, Rosenzweig EB, Girerd B, Montani D, et al. 2013. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 369:351-361.
55. Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, et al. 2006. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27:121-132.
56. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA 3rd, Soubrier F, Trembath RC, Chung WK. 2009. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54:S32-S42.
57. 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, et al. 2001. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 68:92-102.
58. Machado RD, Rudarakanchana N, Atkinson C, Flanagan JA, Harrison R, Morrell NW, Trembath RC. 2003. Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension. Hum Mol Genet 12:3277-3286.
59. Mache CJ, Gamillscheg A, Popper HH, Haworth SG. 2008. Early-life pulmonary arterial hypertension with subsequent development of diffuse pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia type 1. Thorax 63:85-86.
60. Mair KM, Yang XD, Long L, White K, Wallace E, Ewart MA, Docherty CK, Morrell NW, MacLean MR. 2015. Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 191:693-703.
61. Maniatis NA, Shinin V, Schraufnagel DE, Okada S, Vogel SM, Malik AB, Minshall RD. 2008. Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1-/- mice. Am J Physiol Lung Cell Mol Physiol 294:L865-L873.
62. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, et al. 2009. 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.
63. Mercier I, Jasmin JF, Pavlides S, Minetti C, Flomenberg N, Pestell RG, Frank PG, Sotgia F, Lisanti MP. 2009. Clinical and translational implications of the caveolin gene family: lessons from mouse models and human genetic disorders. Lab Invest 89:614-623.
64. Minshall RD, Sessa WC, Stan RV, Anderson RG, Malik AB. 2003. Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol 285:L1179-L1183.
65. Möller T, Leren TP, Eiklid KL, Holmstrøm H, Fredriksen PM, Thaulow E. 2010. A novel BMPR2 gene mutation associated with exercise-induced pulmonary hypertension in septal defects. Scand Cardiovasc J 44:331-336.
66. Murata T, Lin MI, Huang Y, Yu J, Bauer PM, Giordano FJ, Sessa WC. 2007. Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout mice. J Exp Med 204:2373-2382.
67. Nasim MT, Ghouri A, Patel B, James V, Rudarakanchana N, Morrell NW, Trembath RC. 2008. Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet 17:1683-1694.
68. Nasim MT, Ogo T, Ahmed M, Randall R, Chowdhury HM, Snape KM, Bradshaw TY, Southgate L, Lee GJ, Jackson I, Lord GM, Gibbs JS, et al. 2011. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 32:1385-1389.
69. Nishihara A, Watabe T, Imamura T, Miyazono K. 2002. Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. Mol Biol Cell 13:3055-3063.
70. Nohe A, Keating E, Underhill TM, Knaus P, Petersen NO. 2005. Dynamics and interaction of caveolin-1 isoforms with BMP-receptors. J Cell Sci 118:643-650.
71. Pfarr N, Fischer C, Ehlken N, Becker-Grunig T, Lopez-Gonzalez V, Gorenflo M, Hager A, Hinderhofer K, Miera O, Nagel C, Schranz D, Grunig E. 2013. Hemodynamic and genetic analysis in children with idiopathic, heritable, and congenital heart disease associated pulmonary arterial hypertension. Respir Res 14:3.
72. Pfarr N, Szamalek-Hoegel J, Fischer C, Hinderhofer K, Nagel C, Ehlken N, Tiede H, Olschewski H, Reichenberger F, Ghofrani AH, Seeger W, Grunig E. 2011. Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respir Res 12:99.
73. Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Pechoux C, Bogaard HJ, Dorfmuller P, Remy S, Lecerf F, Plante S, Chat S, Fadel E, et al. 2015. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131:1006-1018.
74. Remillard CV, Tigno DD, Platoshyn O, Burg ED, Brevnova EE, Conger D, Nicholson A, Rana BK, Channick RN, Rubin LJ, O'Connor DT, Yuan JX. 2007. Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 292:C1837-C1853.
75. Rigueur D, Brugger S, Anbarchian T, Kim JK, Lee Y, Lyons KM. 2015. The type I BMP receptor ACVR1/ALK2 is required for chondrogenesis during development. J Bone Miner Res 30:733-741.
76. Rosenzweig EB, Morse JH, Knowles JA, Chada KK, Khan AM, Roberts KE, McElroy JJ, Juskiw NK, Mallory NC, Rich S, Diamond B, Barst RJ. 2008. 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.
77. Rudarakanchana N, Flanagan JA, Chen H, Upton PD, Machado R, Patel D, Trembath RC, Morrell NW. 2002. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 11:1517-1525.
78. Ryan J, Bloch K, Archer SL. 2011. Rodent models of pulmonary hypertension: harmonisation with the world health organisation's categorisation of human PH. Int J Clin Pract Suppl:15-34.
79. Shi Y, Massague J. 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685-700.
80. Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R. 2009. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 46:331-337.
81. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, et al. 2013. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34-D41.
82. Smoot LB, Obler D, McElhinney DB, Boardman K, Wu BL, Lip V, Mullen MP. 2009. Clinical features of pulmonary arterial hypertension in young people with an ALK1 mutation and hereditary haemorrhagic telangiectasia. Arch Dis Child 94:506-511.
83. Sobolewski A, Rudarakanchana N, Upton PD, Yang J, Crilley TK, Trembath RC, Morrell NW. 2008. Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. Hum Mol Genet 17:3180-3190.
84. Soubrier F, Chung WK, Machado R, Grunig E, Aldred M, Geraci M, Loyd JE, Elliott CG, Trembath RC, Newman JH, Humbert M. 2013. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 62:D13-D21.
85. Sztrymf B, Coulet F, Girerd B, Yaici A, Jais X, Sitbon O, Montani D, Souza R, Simonneau G, Soubrier F, Humbert M. 2008. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 177:1377-1383.
86. Tenorio J, Navas P, Barrios E, Fernandez L, Nevado J, Quezada CA, Lopez-Meseguer M, Arias P, Mena R, Lobo JL, Alvarez C, Heath K, et al. 2015. A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies. Clin Genet.[Epub ahead of print]
87. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, et al. 2000. 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.
88. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, et al. 2001. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345:325-334.
89. Tuder RM, Archer SL, Dorfmuller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW. 2013. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62:D4-D12.
90. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, et al. 2013. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol 62:D22-D33.
91. Wang H, Cui QQ, Sun K, Song L, Zou YB, Wang XJ, Jia L, Liu X, Gao S, Zhang CN, Hui RT. 2010. Identities and frequencies of BMPR2 mutations in Chinese patients with idiopathic pulmonary arterial hypertension. Clin Genet 77:189-192.
92. Wang G, Knight L, Ji R, Lawrence P, Kanaan U, Li L, Das A, Cui B, Zou W, Penny DJ, Fan Y. 2014. Early onset severe pulmonary arterial hypertension with 'two-hit' digenic mutations in both BMPR2 and KCNA5 genes. Int J Cardiol 177:e167-e169.
93. Wang H, Li W, Zhang W, Sun K, Song X, Gao S, Zhang C, Hui R, Hu H. 2009. Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension. Eur J Hum Genet 17:1063-1069.
94. West J, Cogan J, Geraci M, Robinson L, Newman J, Phillips JA, Lane K, Meyrick B, Loyd J. 2008a. Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genomics 1:45.
95. West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, Rodman DM. 2004. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94:1109-1114.
96. West J, Harral J, Lane K, Deng Y, Ickes B, Crona D, Albu S, Stewart D, Fagan K. 2008b. Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 295:L744-L755.
97. Xu Y, Buikema H, van Gilst WH, Henning RH. 2008. Caveolae and endothelial dysfunction: filling the caves in cardiovascular disease. Eur J Pharmacol 585:256-260.
98. Young KA, Ivester C, West J, Carr M, Rodman DM. 2006. BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 290:L841-L848.
99. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ. 1998. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98:1400-1406.
100. Zhao YY, Liu Y, Stan RV, Fan L, Gu Y, Dalton N, Chu PH, Peterson K, Ross J Jr, Chien KR. 2002. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci USA 99:11375-11380.
101. Zhao YY, Malik AB. 2009. A novel insight into the mechanism of pulmonary hypertension involving caveolin-1 deficiency and endothelial nitric oxide synthase activation. Trends Cardiovasc Med 19:238-242.