Abstract
Pathogenic variants have been identified in 85% of heritable pulmonary arterial hypertension (PAH) patients. These variants were mainly located in the bone morphogenetic protein receptor 2 (BMPR2) gene. However, the penetrance of BMPR2 variants was reduced leading to a disease manifestation in only 30% of carriers. In these PAH patients, further modifiers such as additional pathogenic BMPR2 promoter variants could contribute to disease manifestation. Therefore, the aim of this study was to identify BMPR2 promoter variants in PAH patients and to analyze their transcriptional effect on gene expression and disease manifestation. BMPR2 promoter variants were identified in PAH patients and cloned into plasmids. These were transfected into human pulmonary artery smooth muscle cells to determine their respective transcriptional activity. Nine different BMPR2 promoter variants were identified in seven PAH families and three idiopathic PAH patients. Seven of the variants (c.-575A>T, c.-586dupT, c.-910C>T, c.-930_-928dupGGC, c.-933_-928dupGGCGGC, c.-930_-928delGGC and c.-1141C>T) led to a significantly decreased transcriptional activity. This study identified novel BMPR2 promoter variants which may affect BMPR2 gene expression in PAH patients. They could contribute to disease manifestations at least in some families. Further studies are needed to investigate the frequency of BMPR2 promoter variants and their impact on penetrance and disease manifestation.
Highlights
Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the small pulmonary vessels
In this study we investigated whether bone morphogenetic protein receptor 2 (BMPR2) promoter variants in H/idiopathic PAH (IPAH) serve as second hits, by firstly identifying BMPR2 promoter variants in H/IPAH patients and secondly, functionally characterizing the effect of the variants on BMPR2 gene expression
Seven HPAH families with 53 family members and three IPAH patients were included in this study
Summary
Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the small pulmonary vessels. This results in an increase of pulmonary artery pressure and resistance, eventually progressing to right heart failure [1]. In many forms of PAH, such as heritable (HPAH) or idiopathic PAH (IPAH), genetic defects have been identified [2]. In most cases of HPAH pathogenic variants (mutations) have been identified in the bone morphogenetic protein receptor 2 (BMPR2) gene leading to a loss of gene function [3]. The BMPR2 gene encodes a cell membrane type II receptor of the transforming growth factor-β signaling pathway, which regulates expression of many target genes [4].
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