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.
Choi, Sun Ha MD a; Jung, Youn-Kwan PhD b; Jang, Ji-Ae MS c; Han, Seungwoo MD, PhD a,c,*
98(42):e17594, October 2019.
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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)-[beta] 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-[beta] 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.
Copyright (C) 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.