Download PDF
Semin Respir Crit Care Med 2017; 38(05): 585-595
DOI: 10.1055/s-0037-1606201
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetics of Pulmonary Arterial Hypertension

Joshua D. Chew
1   Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
,
James E. Loyd
2   Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
,
Eric D. Austin
3   Division of Pulmonary, Allergy, and Immunology Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
› Author Affiliations
Further Information

Publication History

Publication Date:
15 October 2017 (online)

    Permissions and Reprints

Abstract

Tremendous progress has been made in understanding the genetics of pulmonary arterial hypertension (PAH) since its description in the 1950s as a primary disorder of the pulmonary vasculature. Heterozygous germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of heritable PAH, and in approximately 20% of cases of idiopathic pulmonary arterial hypertension (IPAH). However, recent advances in gene discovery methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH. Heritable PAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, and female predominance. Biallelic germline mutations in the gene EIF2AK4 are now associated with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Growing genetic knowledge enhances our capacity to pursue and provide genetic counseling, although the issue remains complex given that the majority of carriers of PAH-related mutations will never be diagnosed with the disease.

Keywords

bone morphogenetic protein receptor type 2 - caveolin-1 - KCNK3 - CBLN2 - TBX4 - EIF2AK4 - pulmonary arterial hypertension - genetic modifiers - hereditary hemorrhagic telangiectasia
 

  • References

  • 1 Dresdale DT, Schultz M, Michtom RJ. Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 1951; 11 (06) 686-705
    CrossrefPubMedGoogle Scholar
  • 2 Dresdale DT, Michtom RJ, Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med 1954; 30 (03) 195-207
    PubMedGoogle Scholar
  • 3 Simonneau G, Gatzoulis MA, Adatia I. , et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25, Suppl): D34-D41
    CrossrefPubMedGoogle Scholar
  • 4 Loyd JE, Primm RK, Newman JH. Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis 1984; 129 (01) 194-197
    PubMedGoogle Scholar
  • 5 Soubrier F, Chung WK, Machado R. , et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62 (25, Suppl): D13-D21
    CrossrefPubMedGoogle Scholar
  • 6 Rich S, Dantzker DR, Ayres SM. , et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107 (02) 216-223
    CrossrefPubMedGoogle Scholar
  • 7 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 1997; 95 (12) 2603-2606
    CrossrefPubMedGoogle Scholar
  • 8 Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Familial primary pulmonary hypertension locus mapped to chromosome 2q31-q32. Chest 1998; 114 (1, Suppl): 57S-58S
    CrossrefPubMedGoogle Scholar
  • 9 Thomson JR, Machado RD, Pauciulo MW. , et al. 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; 37 (10) 741-745
    CrossrefPubMedGoogle Scholar
  • 10 Lane KB, Machado RD, Pauciulo MW. , et al; International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 2000; 26 (01) 81-84
    CrossrefPubMedGoogle Scholar
  • 11 Machado RD, Southgate L, Eichstaedt CA. , et al. Pulmonary arterial hypertension: a current perspective on established and emerging molecular genetic defects. Hum Mutat 2015; 36 (12) 1113-1127
    CrossrefPubMedGoogle Scholar
  • 12 Evans JD, Girerd B, Montani D. , et al. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med 2016; 4 (02) 129-137
    CrossrefPubMedGoogle Scholar
  • 13 Trembath RC, Thomson JR, Machado RD. , et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345 (05) 325-334
    CrossrefPubMedGoogle Scholar
  • 14 Harrison RE, Flanagan JA, Sankelo M. , et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 2003; 40 (12) 865-871
    CrossrefPubMedGoogle Scholar
  • 15 Drake KM, Comhair SA, Erzurum SC, Tuder RM, Aldred MA. Endothelial chromosome 13 deletion in congenital heart disease-associated pulmonary arterial hypertension dysregulates SMAD9 signaling. Am J Respir Crit Care Med 2015; 191 (07) 850-854
    CrossrefPubMedGoogle Scholar
  • 16 Drake KM, Dunmore BJ, McNelly LN, Morrell NW, Aldred MA. Correction of nonsense BMPR2 and SMAD9 mutations by Ataluren in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2013; 49 (03) 403-409
    CrossrefPubMedGoogle Scholar
  • 17 Nasim MT, Ogo T, Ahmed M. , et al. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 2011; 32 (12) 1385-1389
    CrossrefPubMedGoogle Scholar
  • 18 Tang H, Desai AA, Yuan JX. ; Application of Whole-Exome Sequencing to the Study of Pathogenic Mechanisms. Genetic insights into pulmonary arterial hypertension. Am J Respir Crit Care Med 2016; 194 (04) 393-397
    CrossrefPubMedGoogle Scholar
  • 19 Austin ED, Ma L, LeDuc C. , et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 2012; 5 (03) 336-343
    CrossrefPubMedGoogle Scholar
  • 20 Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Caveolae and signalling in cancer. Nat Rev Cancer 2015; 15 (04) 225-237
    CrossrefPubMedGoogle Scholar
  • 21 Parton RG, Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol 2007; 8 (03) 185-194
    CrossrefPubMedGoogle Scholar
  • 22 Maniatis NA, Shinin V, Schraufnagel DE. , et al. Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1-/- mice. Am J Physiol Lung Cell Mol Physiol 2008; 294 (05) L865-L873
    CrossrefPubMedGoogle Scholar
  • 23 Zhao YY, Malik AB. A novel insight into the mechanism of pulmonary hypertension involving caveolin-1 deficiency and endothelial nitric oxide synthase activation. Trends Cardiovasc Med 2009; 19 (07) 238-242
    CrossrefPubMedGoogle Scholar
  • 24 Zhao YY, Zhao YD, Mirza MK. , et al. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 2009; 119 (07) 2009-2018
    CrossrefPubMedGoogle Scholar
  • 25 Achcar RO, Demura Y, Rai PR. , et al. Loss of Caveolin and heme oxygenase expression in severe pulmonary hypertension. Chest 2006; 129 (03) 696-705
    CrossrefPubMedGoogle Scholar
  • 26 Zhao YY, Liu Y, Stan RV. , et al. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci U S A 2002; 99 (17) 11375-11380
    CrossrefPubMedGoogle Scholar
  • 27 Wang KY, Lee MF, Ho HC. , et al. Serum caveolin-1 as a novel biomarker in idiopathic pulmonary artery hypertension. BioMed Res Int 2015; 2015: 173970
    PubMedGoogle Scholar
  • 28 Han B, Copeland CA, Kawano Y. , et al. Characterization of a caveolin-1 mutation associated with both pulmonary arterial hypertension and congenital generalized lipodystrophy. Traffic 2016; 17 (12) 1297-1312
    CrossrefPubMedGoogle Scholar
  • 29 Ma L, Roman-Campos D, Austin ED. , et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013; 369 (04) 351-361
    CrossrefPubMedGoogle Scholar
  • 30 Higasa K, Ogawa A, Terao C. , et al. A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension. BMC Pulm Med 2017; 17 (01) 57
    CrossrefPubMedGoogle Scholar
  • 31 Navas P, Tenorio J, Quezada CA. , et al. Molecular analysis of BMPR2, TBX4, and KCNK3 and genotype-phenotype correlations in Spanish patients and families with idiopathic and hereditary pulmonary arterial hypertension. Rev Esp Cardiol (Engl Ed) 2016; 69 (11) 1011-1019
    CrossrefPubMedGoogle Scholar
  • 32 Navas Tejedor P, Tenorio Castaño J, Palomino Doza J. , et al. An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension. Clin Genet 2017; 91 (03) 453-457
    CrossrefPubMedGoogle Scholar
  • 33 Antigny F, Hautefort A, Meloche J. , et al. Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation 2016; 133 (14) 1371-1385
    CrossrefPubMedGoogle Scholar
  • 34 Kerstjens-Frederikse WS, Bongers EM, Roofthooft MT. , et al. TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension. J Med Genet 2013; 50 (08) 500-506
    CrossrefPubMedGoogle Scholar
  • 35 de Jesus Perez VA, Yuan K, Lyuksyutova MA. , et al. Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2014; 189 (10) 1260-1272
    CrossrefPubMedGoogle Scholar
  • 36 Montani D, Lau EM, Dorfmüller P. , et al. Pulmonary veno-occlusive disease. Eur Respir J 2016; 47 (05) 1518-1534
    CrossrefPubMedGoogle Scholar
  • 37 Montani D, Achouh L, Dorfmüller P. , et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008; 87 (04) 220-233
    CrossrefPubMedGoogle Scholar
  • 38 Montani D, Price LC, Dorfmuller P. , et al. Pulmonary veno-occlusive disease. Eur Respir J 2009; 33 (01) 189-200
    CrossrefPubMedGoogle Scholar
  • 39 Eyries M, Montani D, Girerd B. , et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 2014; 46 (01) 65-69
    CrossrefPubMedGoogle Scholar
  • 40 Best DH, Sumner KL, Austin ED. , et al. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest 2014; 145 (02) 231-236
    CrossrefPubMedGoogle Scholar
  • 41 Montani D, Girerd B, Jaïs X. , et al. Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study. Lancet Respir Med 2017; 5 (02) 125-134
    CrossrefPubMedGoogle Scholar
  • 42 Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 2012; 11 (10) 790-811
    CrossrefPubMedGoogle Scholar
  • 43 Feng F, Harper RL, Reynolds PN. BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-β-mediated pulmonary cell signalling. Respirology 2016; 21 (03) 526-532
    CrossrefPubMedGoogle Scholar
  • 44 Larkin EK, Newman JH, Austin ED. , et al. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (09) 892-896
    CrossrefPubMedGoogle Scholar
  • 45 Girerd B, Montani D, Eyries M. , et al. Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir Res 2010; 11: 73
    CrossrefPubMedGoogle Scholar
  • 46 Austin ED, Phillips JA, Cogan JD. , et al. Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respir Res 2009; 10: 87
    CrossrefPubMedGoogle Scholar
  • 47 Rosenzweig EB, Morse JH, Knowles JA. , et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant 2008; 27 (06) 668-674
    CrossrefPubMedGoogle Scholar
  • 48 Elliott CG, Glissmeyer EW, Havlena GT. , et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 2006; 113 (21) 2509-2515
    CrossrefPubMedGoogle Scholar
  • 49 Sztrymf B, Coulet F, Girerd B. , et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008; 177 (12) 1377-1383
    CrossrefPubMedGoogle Scholar
  • 50 Girerd B, Coulet F, Jaïs X. , et al. Characteristics of pulmonary arterial hypertension in affected carriers of a mutation located in the cytoplasmic tail of bone morphogenetic protein receptor type 2. Chest 2015; 147 (05) 1385-1394
    CrossrefPubMedGoogle Scholar
  • 51 Orriols M, Gomez-Puerto MC, Ten Dijke P. BMP type II receptor as a therapeutic target in pulmonary arterial hypertension. Cell Mol Life Sci 2017
    PubMedGoogle Scholar
  • 52 Thomson J, Machado R, Pauciulo M. , et al. Familial and sporadic primary pulmonary hypertension is caused by BMPR2 gene mutations resulting in haploinsufficiency of the bone morphogenetic protein type II receptor. J Heart Lung Transplant 2001; 20 (02) 149
    PubMedGoogle Scholar
  • 53 Machado RD, Pauciulo MW, Thomson JR. , et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001; 68 (01) 92-102
    CrossrefPubMedGoogle Scholar
  • 54 Maquat LE. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 2004; 5 (02) 89-99
    CrossrefPubMedGoogle Scholar
  • 55 Cogan JD, Pauciulo MW, Batchman AP. , et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174 (05) 590-598
    CrossrefPubMedGoogle Scholar
  • 56 Cogan JD, Vnencak-Jones CL, Phillips III JA. , et al. Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med 2005; 7 (03) 169-174
    CrossrefPubMedGoogle Scholar
  • 57 Cogan J, Austin E, Hedges L. , et al. Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. Circulation 2012; 126 (15) 1907-1916
    CrossrefPubMedGoogle Scholar
  • 58 Rudarakanchana N, Flanagan JA, Chen H. , et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 2002; 11 (13) 1517-1525
    CrossrefPubMedGoogle Scholar
  • 59 Hamid R, Cogan JD, Hedges LK. , et al. Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum Mutat 2009; 30 (04) 649-654
    CrossrefPubMedGoogle Scholar
  • 60 Atkinson C, Stewart S, Upton PD. , et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002; 105 (14) 1672-1678
    CrossrefPubMedGoogle Scholar
  • 61 Cogan J, Austin E, Hedges L. , et al. Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. Circulation 2012; 126 (15) 1907-1916
    CrossrefPubMedGoogle Scholar
  • 62 West J, Austin E, Fessel JP, Loyd J, Hamid R. Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension. Drug Discov Today 2014; 19 (08) 1241-1245
    CrossrefPubMedGoogle Scholar
  • 63 Spiekerkoetter E, Tian X, Cai J. , et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 2013; 123 (08) 3600-3613
    CrossrefPubMedGoogle Scholar
  • 64 Spiekerkoetter E, Sung YK, Sudheendra D. , et al. Low-dose FK506 (Tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 192 (02) 254-257
    CrossrefPubMedGoogle Scholar
  • 65 Viales RR, Eichstaedt CA, Ehlken N. , et al. Mutation in BMPR2 promoter: a ‘second hit’ for manifestation of pulmonary arterial hypertension?. PLoS One 2015; 10 (07) e0133042
    CrossrefPubMedGoogle Scholar
  • 66 Maloney JP, Stearman RS, Bull TM. , et al. Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2012; 302 (06) L541-L554
    CrossrefPubMedGoogle Scholar
  • 67 Pierpont ME, Basson CT, Benson Jr DW. , et al; American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115 (23) 3015-3038
    CrossrefPubMedGoogle Scholar
  • 68 Germain M, Eyries M, Montani D. , et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 2013; 45 (05) 518-521
    CrossrefPubMedGoogle Scholar
  • 69 Girerd B, Montani D, Coulet F. , et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181 (08) 851-861
    CrossrefPubMedGoogle Scholar
  • 70 Ghigna MR, Guignabert C, Montani D. , et al. BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension. Eur Respir J 2016; 48 (06) 1668-1681
    CrossrefPubMedGoogle Scholar
  • 71 van der Bruggen CE, Happé CM, Dorfmüller P. , et al. Bone morphogenetic protein receptor type 2 mutation in pulmonary arterial hypertension: a view on the right ventricle. Circulation 2016; 133 (18) 1747-1760
    CrossrefPubMedGoogle Scholar
  • 72 Harper RL, Reynolds AM, Bonder CS, Reynolds PN. BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling. Respirology 2016; 21 (04) 727-733
    CrossrefPubMedGoogle Scholar
  • 73 Brewington J, Clancy JP. Diagnostic testing in cystic fibrosis. Clin Chest Med 2016; 37 (01) 31-46
    PubMedGoogle Scholar
  • 74 Girerd B, Montani D, Jaïs X. , et al. Genetic counselling in a national referral centre for pulmonary hypertension. Eur Respir J 2016; 47 (02) 541-552
    CrossrefPubMedGoogle Scholar
  • 75 Frydman N, Steffann J, Girerd B. , et al. Pre-implantation genetic diagnosis in pulmonary arterial hypertension due to BMPR2 mutation. Eur Respir J 2012; 39 (06) 1534-1535
    CrossrefPubMedGoogle Scholar