Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a progressive condition marked by unusually high blood pressure in the pulmonary artery, which transports blood from the heart to the lungs.1 Although substantial progress has been made in understanding genetics in PAH since 2000, much remains to be uncovered. According to current knowledge, approximately 25% to 30% of cases of idiopathic PAH have an underlying mendelian genetic basis, and these should be classified as heritable PAH (HPAH).2 HPAH, in which a pathogenic mutation is found in one of the known genes, includes familial PAH (PAH that affects 2 or more family members) and simplex PAH (PAH that affects a single individual in a family).3  HPAH is most often caused by mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene; other genes and mechanisms have recently been discovered.4 

Approximately 15% to 20% of individuals with PAH have HPAH. This is a genetic disorder that is inherited in an autosomal-dominant pattern, in which only one copy of a defective gene is required for the disease to manifest. The faulty gene can be inherited from either parent, or a mutation can arise de novo in an affected person. In autosomal-dominant inheritance, each child has a 50% chance of inheriting the defective gene from the affected parent, and the risk is similar for males and females.4

Genetic testing can be used to detect HPAH mutations. Incomplete penetrance of the BMPR2 mutations complicates the diagnosis; disease does not develop in 80% of people with a PAH-associated mutation. Furthermore, the varied expressivity and female preponderance of the genetic mutations indicate that PAH is caused by a combination of genetic and environmental factors.5 

Mutations have been discovered in 10 genes so far: BMPR2, activin receptor-like kinase 1 (ALK1), mothers against decapentaplegic homolog 9 (SMAD9), endoglin 1 (ENG), caveolin 1 (CAV1), potassium channel subfamily K member 3 (KCNK3), BMPR1B, kinase insert domain receptor (KDR), T-box transcription factor 4 (TBX4), and tet-methylcytosine-dioxygenase-2 (TET2).5 

BMPR2 Mutations

BMPR2 is found on the surfaces of many cells, especially in the pulmonary vascular endothelium, where it forms a complex with the type I receptors ALK1 and ALK2. The ALK1/BMPR2 receptor complex, together with ENG as a co-receptor, responds exclusively to the circulating BMP ligands BMP9 and BMP10. High levels of ALK1 and ENG are also found in the pulmonary endothelium, and the requirement for high levels of BMPR2/ALK1 signaling in the endothelium may explain the lung-specific effects of BMPR2 mutations. Loss of BMPR2 contributes to endothelial dysfunction and potentiates a transition from endothelium to mesenchyme.2

Genetic studies indicate that the pulmonary endothelial cell is essential in PAH pathophysiology. Reduced BMPR2 function in other cell types (eg, smooth muscle cells, fibroblasts, and immune cells) also plays a role in PAH pathogenesis.2 Research has shown that BMPR2 mutations are present in 53% to 86% of individuals with a family history of PAH and in 14% to 35% of those with idiopathic PAH.6 According to the studies, the numbers of genetic variants in the idiopathic and familial forms of PAH are identical, and the mutations fall into broad categories. In particular, missense mutations that cause amino acid substitutions account for 25% of PAH-specific variations in BMPR2. Most of the mutations, however, are expected to result in premature protein truncation: nonsense mutations (27%), frameshift mutations (23%), gene rearrangements (14%), and splice-site mutations (10%).6

The BMP pathway is also linked to other, less prevalent PAH mutations. Along with Smad1 and Smad5, Smad8 (encoded by the SMAD9 gene) is a downstream mediator of BMP signaling. SMAD9 mutations result in significant loss of function, implying that microRNAs involved in the regulation of Smad4-independent pathways play a key role in PAH pathophysiology.2

​​CAV1 Mutations

Caveolin 1 is a key component of caveolae (plasma membrane invaginations shaped like flasks) and is found in abundance in endothelial cells. Exome sequencing has identified mutations in CAV1, which encodes caveolin 1. Caveolin 1 depletion reduces BMPR2 membrane localization and signaling. BMPR2 mutations, on the other hand, can cause abnormal caveolar trafficking and intracellular localization. Furthermore, even in individuals who have PAH without heritable mutations, the levels of BMPR2 and caveolin 1 are found to be decreased in the lung tissues.2

Potassium Channel Dysregulation Mutations

KCNK3 mutations have been found in PAH with exome sequencing. KCNK3 encode a potassium channel that helps to determine pulmonary vascular tone by contributing to the membrane potential. BMP signaling regulates potassium channel expression, a finding that suggests a link to known abnormalities of BMPR2 molecules. The discovery of germline mutations in KCNK3 that have deleterious effects on function confirms that potassium channel dysregulation plays a pathogenic role in both familial and idiopathic forms of PAH.2,6


  1. Pulmonary arterial hypertension. MedlinePlus. Accessed March 18, 2022. 
  2. ​​Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019;53(1):1801899. doi:10.1183/13993003.01899-2018
  3. Austin ED, Phillips JA III, Loyd JE. Heritable pulmonary arterial hypertension overview. GeneReviews® [Internet]. Updated December 23, 2020. Accessed March 24, 2022.
  4. Pulmonary arterial hypertension. NORD (National Organization for Rare Disorders). Accessed March 18, 2022.
  5. Lan NSH, Massam BD, Kulkarni SS, Lang CC. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6(2):38. doi:10.3390/diseases6020038
  6. Southgate L, Machado RD, Gräf S, Morrell NW. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol. 2020;17(2):85-95. doi:10.1038/s41569-019-0242-x

Reviewed by Hasan Avcu, MD, on 3/24/2022.