Idiopathic pulmonary arterial hypertension associated with a novel frameshift mutation in the bone morphogenetic protein receptor II gene and enhanced bone morphogenetic protein signaling: A case report.

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by intense remodeling of small pulmonary arteries. Loss-of-function mutation of bone morphogenetic protein receptor II (BMPR2) gene and exaggerated activation of transforming growth factor (TGF)-β signaling play a critical role in this process.

PATIENT CONCERNS AND DIAGNOSIS: We report a novel frameshift mutation (c.117InsT, p.Y40fsX48) of the BMPR2 gene identified in a 19-year-old IPAH patient with syncope. Despite BMPR2 mutation, the phosphorylation of Smad2/3 and Samd1/5/8 was increased in the patient's peripheral blood mononuclear cells, and this event was accompanied by the upregulation of bone morphogenetic protein (BMP) signaling target genes, but not TGF-β signaling target genes. Moreover, we observed an increased expression of other BMPRs, that is, anti-Mullerian hormone type-2 receptor and the activin receptor-like kinases (ALK) 1, ALK3, and ALK6.

INTERVENTIONS AND OUTCOMES: The patient was prescribed a combination of macitentan, sildenafil, and nifedipine, which successfully controlled her symptom of syncope and normalized N-terminal pro-brain natriuretic peptide level after 3 months of medication.

LESSONS: In light of these results, we propose a new pathogenetic mechanism for IPAH, based on enhanced BMP signaling via the functional replacement of mutated BMPR2 by other BMP receptors.