Characteristics of Pulmonary Arterial Hypertension in Affected Carriers of a Mutation Located in the Cytoplasmic Tail of Bone Morphogenetic Protein Receptor Type 2

BACKGROUND: Mutations in BMPR2 encoding bone morphogenetic protein receptor type 2 (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling. METHODS: This cohort study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain. RESULTS: We identified 171 carriers affected with PAH with a mutated BMPR2. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared with other BMPR2 mutation carriers (43.2 +/- 12.1 years and 35.7 +/- 14.6 years, P = .040), a lower pulmonary vascular resistance (13.3 +/- 3.5 and 17.4 +/- 6.7, P = .023), and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, P = .02). No statistically significant differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain. CONCLUSIONS: Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared with other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of these BMPR2 mutations in BMPRII signaling pathways and their possible role in pulmonary arterial remodeling.