The role of genetics in pulmonary arterial hypertension

Abstract

Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH) is a rare disease characterized by proliferation and occlusion of small pulmonary arterioles, leading to progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, and right ventricular failure. Historically, it has been associated with a high mortality rate, although, over the last decade, treatment has improved survival. PAH includes idiopathic PAH (IPAH), heritable PAH (HPAH), and PAH associated with certain medical conditions. The aetiology of PAH is heterogeneous, and genetics play an important role in some cases. Mutations in BMPR2, encoding bone morphogenetic protein receptor 2, a member of the transforming growth factor-β superfamily of receptors, have been identified in 70% of cases of HPAH, and in 10-40% of cases of IPAH. Other genetic causes of PAH include mutations in the genes encoding activin receptor-like type 1, endoglin, SMAD9, caveolin 1, and potassium two-pore-domain channel subfamily K member 3. Mutations in the gene encoding T-box 4 have been identified in 10-30% of paediatric PAH patients, but rarely in adults with PAH. PAH in children is much more heterogeneous than in adults, and can be associated with several genetic syndromes, congenital heart disease, pulmonary disease, and vascular disease. In addition to rare mutations as a monogenic cause of HPAH, common variants in the gene encoding cerebellin 2 increase the risk of PAH by approximately two-fold. A PAH panel of genes is available for clinical testing, and should be considered for use in clinical management, especially for patients with a family history of PAH. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: BMPR2; CAV1; KCNK3; TBX4; TGF-β; genetics.

Figure 1

Typical pathological features of PAH. A, B: Lung biopsy from a PAH patient with a CAV1 mutation (grade I and II). H&E staining shows medial thickening of small pulmonary arteries (Panel A, arrows), and pulmonary vascular smooth muscle cell proliferation -- confirmed by immunohistochemical staining of alpha smooth muscle actin (Panel B, arrows) [51]. C, D: Lung tissue from a PAH patient with a KCNK3 mutation. Panel C shows intimal proliferation, fibrosis (arrow head) and recanalization (asterisk), with an adjacent angiomatoid lesion (arrow) typical of pulmonary arterial hypertension (grade III). Grade IV disease includes plexiform lesions characterized by endothelial and intimal proliferation (Panel D, arrow) [61].

Figure 2

PAH genes and signaling pathways. BMP ligands, such as BMP9, bind to BMPR2. Upon ligand binding, BMPR2 phosphorylates BMPR1, including ALK1, ALK2, ALK3 or ALK6 (ACVRL1, ACVR2, BMPR1A or BMPR1B respectively). The ligand-receptor complex phosphorylates SMAD1/5/8 and subsequently phosphorylates SMAD4. The phosphorylated SMADs translocate to the nucleus and regulate expression of target genes. TGF-β ligands, such as ENG, bind TGFβR2 to phosphorylate TGFβRI, including ALK1 (ACVRL1) and ALK5 (TGFBR1). The complex phosphorylates SMAD2/3 which phosphorylates SMAD4 and translocates to the nucleus. CAV1 interacts with BMPR2 to prevent vascular proliferation. BMPR2 phosphorylates SRC, which regulates cell proliferation or regulates CAV1 to activate PI3K/AKT activity. KCNK3 encodes a 2-pore potassium channel and regulates membrane potential as well as vascular tone. TBX4 regulates fibroblast growth factor 10 (FGF10), which binds with fibroblast growth factor receptor 2 (FGFR2) to regulate development in lung.