Important pulmonary arterial hypertension (PAH) susceptibility genes
| Genes | Overview | References |
| BMPR2 | Member of the TGF-β receptor superfamily Ubiquitously expressed, important for vascular homeostasis Autosomal dominant inheritance, with incomplete penetrance (estimated 14% penetrance in male carriers and 42% in female carriers) Mutations associated with paediatric and adult PAH | [22] |
| ALK1/ACVRL1 | Member of the TGF-β receptor superfamily Forms a heteromeric complex with BMPR2 Causes PAH associated with HHT Mutations are associated with paediatric and adult PAH | [24, 25] |
| Endoglin | Member of the TGF-β receptor superfamily Co-receptor to BMPR2/ALK1 receptors Causes PAH associated with HHT | [25] |
| SMAD9 | Important protein in the BMP signalling pathway Encodes the transcription factor Smad8 | [25] |
| BMP9/GDF2 | Mediator in the BMP signalling pathway Encodes the BMP9 ligand | [22] |
| TBX4 | Associated with small patella/coxopodopatellar syndrome Mutations are associated with paediatric and adult PAH Its precise role in the development of PAH is unclear | [25, 26] |
| CAV1 | Encodes the protein caveolin-1, which is responsible for the integrity of caveolae; these are specialised invaginations in endothelial plasma membranes that are rich in cell surface receptors, including BMPR2 and endothelial nitric oxide synthase This is important for vascular homeostasis and is implicated in proliferative, apoptotic signalling Mutations in this gene are a rare cause of HPAH | [22, 25] |
| KCNK3 | Also called TASK-1 (TWIK-related acid-sensitive K+ channel 1) This was the first identified channelopathy in PAH Encodes a pH-sensitive potassium channel, which is important for the regulation of plasma membrane resting potential Reduced function of KCNK3 in PAH may affect vascular tone | [25] |
| EIF2AK4 | Encodes GCN2 (general control nonderepressible 2) which is a serine-threonine kinase with a role in cellular adaptation to stress and amino acid deprivation Mutations are associated with paediatric and adult PAH Autosomal recessive inheritance, with near complete penetrance Results in pulmonary veno-occlusive disease/PCH The exact mechanism by which this leads to pulmonary vascular disease is unclear | [27] |
An overview of gene mutations in heritable PAH (HPAH). These mutations are inherited in an autosomal dominant fashion, with reduced penetrance, apart from EIF2AK4 (eukaryotic translation initiation factor 2α kinase 4), which is inherited in an autosomal recessive pattern, with suspected near complete penetrance. BMPR2: bone morphogenetic protein receptor 2; TGF-β: transforming growth factor-β; ALK1/ACVRL1: activin A receptor-like type 1; HHT: hereditary haemorrhagic telangiectasia; SMAD: small mothers against decapentaplegic; BMP: bone morphogenetic protein; GDF2: growth and differentiation factor 2; TBX4: T-box 4; CAV1: caveolin-1; KCNK3: potassium channel two-pore domain subfamily K member 3; PCH: pulmonary capillary haemangiomatosis.