Abstract
Heritable pulmonary arterial hypertension (HPAH) and hereditary hemorrhagic telangiectasia (HHT) are rare diseases with autosomal dominant inheritance. HHT is often found to be the underlying cause of pulmonary arteriovenous malformations (PAVMs). Mutations in BMPR2, ACVRLK1, ENG, SMAD9, CAV1, and KCNK3 have been identified in cases of HPAH. Mutations in ACVRLK1, ENG, and SMAD4 have been identified in cases of HHT. The average penetrance of BMPR2 mutations is only 30% in HPAH. In contrast, the average penetrance of ACVRLK1 and ENG mutations is almost 100% in HHT, but the affected organs often differ within the family. It is likely that there are additional genes and genetic/epigenetic or environmental modifiers such as hormones, inflammation, hypoxia, medications/drugs, or infections that play important roles to form phenotypes in HPAH and HHT. Further research is required to fully elucidate these potential mechanisms.
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Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(Suppl):D42–50.
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(Suppl):D34–41.
Tuder RM, Marecki JC, Richter A, et al. Pathology of pulmonary hypertension. Clin Chest Med. 2007;28:23–42.
Tamura Y, Kumamaru H, Satoh T, et al. Effectiveness and outcome of pulmonary arterial hypertension-specific therapy in Japanese patients with pulmonary arterial hypertension. Circ J. 2017;82(1):275–82.
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;30:195–207.
Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000;26:81–4.
Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737–44.
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;40:865–71.
McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8:345–51.
Shintani M, Yagi H, Nakayama T, et al. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet. 2009;46:331–7.
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;5:336–43.
Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351–61.
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;174:590–8.
Aldred MA, Vijayakrishnan J, James V, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat. 2006;27:212–3.
Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66–7.
Cottin V, Chinet T, Lavole A, et al. Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. Medicine (Baltimore). 2007;86:1–17.
Vorselaars VM, Velthuis S, Snijder RJ, et al. Pulmonary hypertension in hereditary haemorrhagic telangiectasia. World J Cardiol. 2015;7:230–7.
Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13:189–95.
Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363:852–9.
Gore B, Izikki M, Mercier O, et al. Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension. PLoS One. 2014;9:e100310.
Aschner Y, Downey GP. Transforming growth factor-β: master regulator of the respiratory system in health and disease. Am J Respir Cell Mol Biol. 2016;54:647–55.
Ma L, Chung WK. The genetic basis of pulmonary arterial hypertension. Hum Genet. 2014;133:471–9.
Upton PD, Davies RJ, Trembath RC, et al. Bone morphogenetic protein (BMP) and activine type 2 receptors balance BMP9 signals mediated by activing receptor-like kinase-1 in human pulmonary artery endothelial cells. J Biol Chem. 2009;284:15794–804.
Quest AF, Leyton L, Parraga M. Caveolins, caveolae, and lipid rafts in cellular transport, signaling, and disease. Biochem Cell Biol. 2004;82:129–44.
Drab M, Verkade P, Elger M, et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science. 2001;293:2449–52.
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;4:129–37.
Isobe S, Kataoka M, Aimi Y, et al. Improved survival of patients with pulmonary arterial hypertension with BMPR2 mutations in the last decade. Am J Respir Crit Care Med. 2016;193:1310–4.
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;181:851–61.
Letteboer TG, Mager JJ, Snijder RJ, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet. 2006;43:371–7.
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Sugiura, T., Tatsumi, K. (2018). Pulmonary Vascular Diseases: Pulmonary Hypertension and HHT—What Are the Roles of Genetic Factors in the Pathogenesis of Pulmonary Vascular Diseases?. In: Kaneko, T. (eds) Clinical Relevance of Genetic Factors in Pulmonary Diseases. Respiratory Disease Series: Diagnostic Tools and Disease Managements. Springer, Singapore. https://doi.org/10.1007/978-981-10-8144-6_9
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DOI: https://doi.org/10.1007/978-981-10-8144-6_9
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