Molecular Genetics of Pulmonary Hypertension

Abstract

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‐β) 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‐β 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‐β 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.

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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.

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Strachan T and Read AP (2010) Human Molecular Genetics, 4th edn. London: Garland Science, Taylor & Francis Group.

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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]