BMPR2

BMPR2, or bone morphogenetic protein receptor type II, is a transmembrane serine/threonine kinase that mediates BMP signaling in the TGF-β superfamily. It contains an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular kinase domain that initiates downstream signaling when activated.

BMPR2 forms a receptor complex with type I BMP receptors, such as ALK1/ACVRL1 or BMPR1A/BMPR1B. In canonical signaling, ligand-bound BMPR2 phosphorylates the type I receptor, triggering phosphorylation of SMAD1/5/8. These SMADs partner with SMAD4 to regulate gene transcription in the nucleus; non-SMAD pathways can also be engaged.

Clinical significance: BMPR2 mutations are the major genetic cause of heritable and familial pulmonary arterial hypertension (PAH). Mutations reduce BMP signaling, promoting endothelial dysfunction and excessive pulmonary artery smooth muscle proliferation. BMPR2 variants show incomplete penetrance and variable expressivity.

Genetics and variant spectrum: The BMPR2 gene is located on chromosome 2q33.3. Pathogenic variants include truncating and missense mutations, splice-site alterations, and deletions, often resulting in haploinsufficiency or dominant-negative effects and predisposition to PAH.

Role beyond PAH: BMP signaling via BMPR2 also influences vascular development and homeostasis, with effects on endothelial cell biology and vascular remodeling in the lung.

Research and models: Animal and cellular models with Bmpr2 mutations are used to study PAH pathogenesis and to test therapies aimed at restoring BMP signaling in the pulmonary vasculature.