Table 6.
Genes underlying PAH that are validated in multiple cohorts
| Gene | Protein | Cellular and Molecular Function | Reference(s) |
|---|---|---|---|
| Ligand | |||
| GDF2 (BMP9) | Growth differentiation factor 2 or bone morphogenetic protein 9 | Activates TGF-β family receptors (e.g., ACVRL1) and SMAD family transcription factors involved in gene expression and angiogenesis | (264) |
| BMP10 | Bone morphogenetic protein 10 | Activates TGF-β family receptors and SMAD family transcription factors that regulate gene expression and cell proliferation | (264, 531) |
| FBLN2 | Fibulin 2 | An extracellular matrix protein that binds fibronectin and Ca2+. Its function is involved in organ development. | (532) |
| PDGFD | Platelet-derived growth factor D | A growth factor involved in embryonic development as well as cell proliferation, migration, survival, and chemotaxis | (532) |
| Membrane receptor and transporter | |||
| BMPR2 | Bone morphogenetic protein (BMP) receptor type II | A tyrosine kinase receptor activated by BMP family of ligands | (529, 530, 533–536) |
| ACVRL1 | Activin receptor-like kinase 1 | A tyrosine kinase receptor activated by the TGF-β superfamily of ligands | (505, 537–539) |
| ENG | Endoglin | A glycoprotein as a component of the TGF-β receptor complex | (483, 537, 538) |
| Cav1 | Caveolin 1 | A scaffolding protein as the main component of the caveolae plasma membrane | (395, 483) |
| SLC6A4 | Serotonin (5-HT) transporter | Transports extracellular 5-HT (a neurotransmitter and vasoconstrictor) into the cytoplasm | (540, 541) |
| Ion channel and transporter | |||
| KCNK3 (or TASK1) | Two-pore domain K+ channel subfamily K member | A pH-sensitive K+ channel involved in generating background K+ current and regulating membrane potential | (483–485) |
| ABCC8 | Sulfonylurea receptor 1 (SUR1) | Forms ATP-sensitive K+ channels with inward-rectifier K+ channel subunits that are inhibited by intracellular ATP | (448, 490, 495, 496) |
| AQP1 | Aquaporin 1 | Molecular water channel and cGMP-gated nonselective cation channel that allows water, H+, , NO, glycerol, CO2, and O2 to go through according to the electrochemical gradient | (542–547) |
| ATP13A3 | ATPase 13A3 | P-type ATPase family protein that transports cations across membrane | (531, 542, 548) |
| TRPC6 | Transient receptor potential canonical channel 6 | Forms receptor-operated and DAG-activated cation channels for ligand- and mechanical force-mediated Ca2+ influx | (123, 549, 550) |
| Signaling protein and kinase | |||
| EIF2AK4 | Eukaryotic translation initiation factor 2α kinase 4 | Phosphorylates the α-subunit of EIF2 (eukaryotic translation initiation factor-2) and regulates protein expression | (531, 551–553) |
| SMAD1 | SMAD family member 1 | Transduces signals from BMP receptors | (554) |
| SMAD4 | SMAD family member 4 | Transduces signals from TGF-β family receptors | (554) |
| SMAD8 | SMAD family member 8 | Transduces signals from BMP receptors | (555) |
| SMAD9 | SMAD family member 9 | Transduces signals from TGF-β family receptors | (554, 556) |
| Transcription factor | |||
| TBX4 | T-Box transcription factor 4 | Transcriptional regulation of genes involved in the lung development or genesis | (532, 557–559) |
| Sox17 | SRY-box transcription factor 17 | Transcriptional regulation of genes involved in Wnt signaling and embryonic development | (203, 560) |
DAG, diacylglycerol; NO, nitric oxide; PAH, pulmonary arterial hypertension.