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Case Reports
, 98 (42), e17594

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

Case Reports

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

Sun Ha Choi et al. Medicine (Baltimore).


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.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this article.


Figure 1
Figure 1
Identification of a frameshift mutation in exon 2 of the BMPR2 gene. (A) Exon 2 sequencing reveals a heterozygous addition of T at position 117 in the coding sequence, indicated by red arrowhead. (B) This addition made a shift in the grouping of 3 bases, the amino acid changes, and stop codon at amino acid position 48. (C) Schematic structure of the BMPR2 protein. The mutation site indicated by the red arrowhead is located in the extracellular ligand-binding domain. BMPR2 = bone morphogenetic protein receptor II.
Figure 2
Figure 2
BMPR2 expression and enhanced BMP and TGF-β signaling. (A) Western blot analysis of BMPR2, phosphorylated Smad1/5/8, and Smad2/3, Erk1/2, and p38 MAP kinase. PBMCs were cultured with BMP2 (200 ng/mL), TGF-β (20 ng/mL), and PMA (100 nM) for 24 h to stimulate Smad signaling. C stands for control and P for patient. (B) RNA expression of BMPR2, the BMP target genes, ID1, SMAD6, and STAT1, and the TGF-β-target genes, Atf4, Gadd45b, Emp1, and Myc. PBMCs were cultured in α-MEM-based complete medium for 6 h and harvested for the real-time qPCR. P < .05 patient versus controls. BMPR2 = bone morphogenetic protein receptor II, PBMCs = peripheral blood mononuclear cells, qPCR = quantitative polymerase chain reaction, TGF-β = transforming growth factor-β.
Figure 3
Figure 3
Aberrant expression of BMP receptors and implications for IPAH pathogenesis. (A) RNA expression of type I and II BMP receptors. PBMCs from the IPAH patient and controls were cultured for 6 h in complete medium. (B) Protein level of AMHR2, BMPR1A (ALK3), and BMPR1B (ALK6) in PBMCs treated with growth factors for 24 h. C stands for control and P for patient. (C) Schematic diagram of BMP receptor expression that may result in the enhanced BMP signaling in IPAH. The loss-of-function mutation of BMPR2 is associated with increased expression of other receptors of the TGF-β superfamily, that is, AMHR2 (type II BMPR), as well as ALK1, ALK3, and ALK6 (type I BMPRs), leading to enhanced activation of both Smad1/5/8 and Smad2/3, and increased BMP signaling. ALK = activin receptor-like kinases, AMHR2 = anti-Mullerian hormone receptor 2, BMPR = bone morphogenetic protein receptor, IPAH = idiopathic pulmonary arterial hypertension, PBMCs = peripheral blood mononuclear cells, TGF-β =  = transforming growth factor-β.

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