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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.

ABSTRACT: 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)-? 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-? 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.

SUBMITTER: Choi SH

PROVIDER: S-EPMC6824762 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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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 SH Jung Youn-Kwan YK Jang Ji-Ae JA Han Seungwoo S

Medicine 20191001 42

<h4>Rationale</h4>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.<h4>Patient concerns and diagnosis</h4>We report a novel frameshift mutation (c.117InsT, p.Y40fsX48) of the BMPR2 gene identified in a 19-year-old IPAH patient with syncop ...[more]

PMID: 31626133

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Project description:Pulmonary arterial hypertension is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3'-deoxy-3'-[18F]-fluorothymidine (18FLT) positron emission tomography (PET) scanning was increased in pulmonary arterial hypertension patients, hence providing a possible biomarker for pulmonary arterial hypertension as it reflects vascular cell hyperproliferation in the lung. This study sought to validate 18FLT-PET in an expanded cohort of pulmonary arterial hypertension patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 mutation carriers. 18FLT-PET scanning was performed in 21 pulmonary arterial hypertension patients (15 hereditary pulmonary arterial hypertension and 6 idiopathic pulmonary arterial hypertension), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung 18FLT k3 phosphorylation among pulmonary arterial hypertension patients, unaffected bone morphogenetic protein receptor type 2 mutation carriers and healthy controls. Lung 18FLT uptake did not correlate with haemodynamic or clinical parameters in pulmonary arterial hypertension patients. Sequential 18FLT-PET scanning in three patients demonstrated uneven regional distribution in 18FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. We did not detect significantly increased lung 18FLT uptake in pulmonary arterial hypertension patients, nor in the unaffected bone morphogenetic protein receptor type 2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human 18FLT report may be explained by a small sample size previously and we observed large variation of lung 18FLT signals between patients, challenging the application of 18FLT-PET as a biomarker in the pulmonary arterial hypertension clinic.

Project description:Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic characteristics in three groups: COPD non-PH, COPD-PH, and IPAH, respectively. Histological specimens were examined by a cardiovascular pathologist blinded to clinical and hemodynamic data. Pathological alterations of pulmonary veins were present in all hemodynamic groups, with the following incidences of VH grade 0/1/2: 34/66/0% in COPD non-PH; 19/71/10% in COPD-PH; and 11/61/28% in IPAH. In COPD, explorative correlation analysis of venous remodeling suggested a modest positive correlation with systolic and mean pulmonary artery pressure ( P = 0.032, respectively) and an inverse modest correlation with diffusion capacity for carbon monoxide ( P = 0.027). In addition, venous remodeling correlated positively with the degree of arterial remodeling ( P = 0.014). In COPD-PH and IPAH, advanced forms of pulmonary venous remodeling are present, emphasizing that the disease is not exclusively restricted to arterial lesions. In addition, venous remodeling may be related to the hemodynamic severity, but more rigorous analysis is required to clearly define potential relationships.

Dataset Information

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.

Publications

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.

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