Molecular Genetics of Pulmonary Hypertension

Laura Southgate, King's College London, London, UK
Rajiv D Machado, King's College London, London, UK

Published online: December 2011

DOI: 10.1002/9780470015902.a0022444

Pulmonary arterial hypertension (PAH) is a progressive vascular disorder with high levels of mortality and morbidity. Approximately 10% of PAH patients have a family history of disease in which the disease segregates as an autosomal dominant trait. Employing a classical positional cloning approach comprising microsatellite linkage analysis and candidate gene screening, the causal gene for PAH in families was identified as BMPR2, encoding a type II receptor of the transforming growth factor beta (TGF-) signalling network. Subsequent functional investigation has revealed the molecular mechanisms of disease and together with protein–protein interaction studies underpinned key factors in disease progression. Taken together with the recent discovery of rare mutations in additional members of the TGF- family these data have served to underline the central importance of this pathway in the development and maintenance of the pulmonary vasculature.

Key Concepts:

  • Pulmonary arterial hypertension specifically constricts and obstructs the small arteries of the lung.
  • Vasoconstriction and arteriole occlusion is caused by the uncontrolled proliferation of pulmonary vascular endothelial and smooth muscle cells.
  • In the absence of treatment death occurs as a result of right heart failure.
  • Twice as many females as males are affected.
  • The major genetic factor underlying disease is heterozygous mutations of BMPR2.
  • The predominant molecular mechanism of disease is haploinsufficiency.
  • BMPR2 mutations have been identified in nonfamilial PAH and, on rare occasions, PAH associated with other disorders and risk factors.
  • The identification of rare mutations in additional members of the TGF- pathway point to the importance of this signalling system in the maintenance of the pulmonary vascular bed.
  • The genetic architecture of pulmonary hypertension remains to be fully elucidated.

Keywords: pulmonary arterial hypertension; BMPR2; haploinsufficiency; ALK1; massively parallel sequencing

Figure 1. Spectrum of truncating mutations of BMPR2 in HPAH. The central bar depicts the cDNA structure of BMPR2 subdivided by 13 exons encoding the four functional domains indicated in the bar beneath. The symbols above and below refer to the type of truncating mutation identified in disease and the presence of recurrent mutations. Symbols are explained in the boxed key. The horizontal lines indicate the presence and size of gene rearrangements detected across the gene. Reproduced from Machado RD, Trembath RC and Morrell NW (2011) Genetics of severe pulmonary hypertension. In: Voelkel NF (ed.) Pulmonary Hypertension: The Present and Future. USA: People's Medical Publishing House (PMPH), with kind permission from PMPH-USA, Ltd.
Figure 2. Amino acid substitutions of the kinase domain in HPAH. The central bar presents an expanded view of exons 5–11, encoding the 12 highly conserved kinase subdomains of BMPR-II. Asterisks identify amino acid residues indispensible to receptor activity. Identified amino acid substitutions in HPAH are indicated. Reproduced from Machado RD, Trembath RC and Morrell NW (2011) Genetics of severe pulmonary hypertension. In: Voelkel NF (ed.) Pulmonary Hypertension: The Present and Future. USA: People's Medical Publishing House (PMPH), with kind permission from PMPH-USA, Ltd.
Figure 3. Schematic displaying the key clinical and genetic elements in PAH. Although BMPR2 (in red) constitutes the major genetic factor underlying the disease, the existence of additional genetic susceptibility loci combined with complex features of disease point to as yet missing heritability, as indicated by the central piece of the puzzle.
close
 References
    Abdalla SA, Cymerman U, Rushlow D et al. (2005) Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Human Mutation 25: 320–321.
    Aldred MA, Machado RD, James V et al. (2007) Characterization of the BMPR2 5¢-untranslated region and a novel mutation in pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 176: 819–824.
    Aldred MA, Vijayakrishnan J, James V et al. (2006) BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Human Mutation 27: 212–213.
    Austin ED, Phillips JA, Cogan JD et al. (2009) Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respiratory Research 10: 87.
    Bayrak-Toydemir P, McDonald J, Akarsu N et al. (2006) A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. American Journal of Medical Genetics Part A 140: 2155–2162.
    Berg JN, Gallione CJ, Stenzel TT et al. (1997) The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. American Journal of Human Genetics 61: 60–67.
    Deng Z, Morse JH, Slager SL et al. (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. American Journal of Human Genetics 67: 737–744.
    Elliott CG, Glissmeyer EW, Havlena GT et al. (2006) Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 113: 2509–2515.
    Foletta VC, Lim MA, Soosairajah J et al. (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. Journal of Cell Biology 162: 1089–1098.
    Fujiwara M, Yagi H, Matsuoka R et al. (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. Circulation Journal 72: 127–133.
    Gaine SP and Rubin LJ (1998) Primary pulmonary hypertension. Lancet 352: 719–725.
    Garamszegi N, Dore JJ Jr, Penheiter SG et al. (2001) Transforming growth factor beta receptor signaling and endocytosis are linked through a COOH terminal activation motif in the type I receptor. Molecular Biology of the Cell 12: 2881–2893.
    Greenwald J, Fischer WH, Vale WW et al. (1999) Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase. Nature Structural Biology 6: 18–22.
    Hanks SK and Hunter T (1995) Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB Journal 9: 576–596.
    Harrison RE, Flanagan JA, Sankelo M et al. (2003) Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. Journal of Medical Genetics 40: 865–871.
    Humbert M, Deng Z, Simonneau G et al. (2002) BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. European Respiratory Journal 20: 518–523.
    Humbert M, Sitbon O, Chaouat A et al. (2006) Pulmonary arterial hypertension in France: results from a national registry. American Journal of Respiratory and Critical Care Medicine 173: 1023–1030.
    Katta S, Kaur I and Chakrabarti S (2009) The molecular genetic basis of age-related macular degeneration: an overview. Journal of Genetics 88: 425–449.
    Kawabata M, Chytil A and Moses HL (1995) Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor. Journal of Biological Chemistry 270: 5625–5630.
    Koehler R, Grunig E, Pauciulo MW et al. (2004) Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. Journal of Medical Genetics 41: e127.
    Ku CS, Naidoo N and Pawitan Y (2011) Revisiting Mendelian disorders through exome sequencing. Human Genetics 129: 351–370.
    Lander ES (2011) Initial impact of the sequencing of the human genome. Nature 470: 187–197.
    Lane KB, Machado RD, Pauciulo MW et al. (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nature Genetics 26: 81–84.
    Liu F, Ventura F, Doody J et al. (1995) Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Molecular and Cellular Biology 15: 3479–3486.
    Loyd JE, Butler MG, Foroud TM et al. (1995) Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 152: 93–97.
    Machado RD, Eickelberg O, Elliott CG et al. (2009) Genetics and genomics of pulmonary arterial hypertension. Journal of the American College of Cardiology 54: S32–S42.
    Machado RD, Pauciulo MW, Fretwell N et al. (2000) A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium. Genomics 68: 220–228.
    Machado RD, Pauciulo MW, Thomson JR et al. (2001) BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. American Journal of Human Genetics 68: 92–102.
    Machado RD, Rudarakanchana N, Atkinson C et al. (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. Human Molecular Genetics 12: 3277–3286.
    Mamanova L, Coffey AJ, Scott CE et al. (2010) Target-enrichment strategies for next-generation sequencing. Nature Methods 7: 111–118.
    Miyazono K, Kamiya Y and Morikawa M (2010) Bone morphogenetic protein receptors and signal transduction. Journal of Biochemistry 147: 35–51.
    Morisaki H, Nakanishi N, Kyotani S et al. (2004) BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. Human Mutation 23: 632.
    Morse JH, Jones AC, Barst RJ et al. (1997) Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31–q32. Circulation 95: 2603–2606.
    Nasim Mt, Ogo T, Ahmed M et al. (2011) Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Human Mutation (DOI: 10.1002/humu.21605).
    Nichols WC, Koller DL, Slovis B et al. (1997) Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nature Genetics 15: 277–280.
    Nishihara A, Watabe T, Imamura T et al. (2002) Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. Molecular Biology of the Cell 13: 3055–3063.
    Roberts KE, McElroy JJ, Wong WP et al. (2004) BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. European Respiratory Journal 24: 371–374.
    Rudarakanchana N, Flanagan JA, Chen H et al. (2002) Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Human Molecular Genetics 11: 1517–1525.
    Runo JR and Loyd JE (2003) Primary pulmonary hypertension. Lancet 361: 1533–1544.
    Sankelo M, Flanagan JA, Machado R et al. (2005) BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Human Mutation 26: 119–124.
    Shintani M, Yagi H, Nakayama T et al. (2009) A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. Journal of Medical Genetics 46: 331–337.
    Shovlin CL, Hughes JM, Scott J et al. (1997) Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. American Journal of Human Genetics 61: 68–79.
    Simonneau G, Robbins IM, Beghetti M et al. (2009) Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 54: S43–S54.
    Sztrymf B, Coulet F, Girerd B et al. (2008) Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. American Journal of Respiratory and Critical Care Medicine 177: 1377–1383.
    Thomson JR, Machado RD, Pauciulo MW 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. Journal of Medical Genetics 37: 741–745.
    Trembath RC, Thomson JR, Machado RD et al. (2001) Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. New England Journal of Medicine 345: 325–334.
    Vincent P, Plauchu H, Hazan J et al. (1995) A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q. Human Molecular Genetics 4: 945–949.
 Further Reading
    Hassoun PM, Mouthon L, Barberà JA et al. (2009) Inflammation, growth factors, and pulmonary vascular remodeling. Journal of the American College of Cardiology 54: S10–S19.
    book Machado RD and Trembath RC (2011) "Chapter 3: genetics". In: Gatzoulis MA (ed.) Oxford Cardiology Library: Pulmonary Arterial Hypertension, pp. 31–44. Oxford: Oxford University Press.
    Massague J (1998) TGF-beta signal transduction. Annual Review of Biochemistry 67: 753–791.
    Metzker ML (2010) Sequencing technologies – the next generation. Nature Reviews Genetics 11: 31–46.
    Morrell NW, Adnot S, Archer SL et al. (2009) Cellular and molecular basis of pulmonary arterial hypertension. Journal of the American College of Cardiology 54: S20–S31.
    Rider CC and Mulloy B (2010) Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists. Biochemical Journal 429: 1–12.
    book Strachan T and Read AP (2010) Human Molecular Genetics, 4th edn. London: Garland Science, Taylor & Francis Group.

Related Sub-Topics:

Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Gene Mapping by Disease Association
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Molecular Genetics of Pulmonary Hypertension
 
How to Cite close
Southgate, Laura, and Machado, Rajiv D(Dec 2011) Molecular Genetics of Pulmonary Hypertension. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022444]