The genetics of pulmonary arterial hypertension in the post-BMPR2 era

Abstract

Pulmonary arterial hypertension (PAH) is a rapidly progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. The most common single culprit gene known is BMPR2, and animal models of the disease in several forms exist. There is a wealth of genetic data regarding modifiers of disease expression, penetrance, and severity. Despite the rapid accumulation of data in the last decade, a complete picture of the molecular pathogenesis of PAH leading to novel therapies is lacking. In this review, we attempt to summarize the current understanding of PAH from the genetic perspective. The most recent PAH demographics are discussed. Heritable PAH in the post-BMPR2 era is examined in detail as the most robust model of PAH genetics in both animal models and human pedigrees. Important downstream molecular pathways and modifiers of disease expression are reviewed in light of what is known about PAH pathogenesis. Current and emerging therapies are examined in light of genetic data. The role of genetic testing in PAH in the post-BMPR2 era is discussed. Finally, directions for future investigations that ideally will fulfill the promise of novel therapeutic or preventive strategies are discussed.

Keywords: BMPR2; heritable pulmonary arterial hypertension; idiopathic pulmonary arterial hypertension; pulmonary arterial hypertension; right ventricle.

Figure 1

Updated pedigree of the 14^th family reported in the literature with HPAH. Symbols are standard for pedigree analysis and are explained in the figure caption. This family carries a mutation in the ligand-binding domain of BMPR2.

Figure 2

Simplified canonical TGF-β/BMP signaling and non-canonical signaling unique to BMPR2. The dashed line delineates canonical TGF-β signaling (on the left) from some of the pathways interacting with BMPR2via its long cytoplasmic tail.

Figure 3

Diagram of pre- and post-test probabilities for developing HPAH in an unaffected family member, and the mathematical impact of testing for BMPR2mutation.