| Summary: | 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 (<i>BMPR2</i><span style="font-variant: small-caps;">)</span> gene. However, the penetrance of <i>BMPR2</i> variants was reduced leading to a disease manifestation in only 30% of carriers. In these PAH patients, further modifiers such as additional pathogenic <i>BMPR2</i> promoter variants could contribute to disease manifestation. Therefore, the aim of this study was to identify <i>BMPR2</i> promoter variants in PAH patients and to analyze their transcriptional effect on gene expression and disease manifestation. <i>BMPR2</i> 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 <i>BMPR2</i> 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 <i>BMPR2</i> promoter variants which may affect <i>BMPR2</i> 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 <i>BMPR2</i> promoter variants and their impact on penetrance and disease manifestation.
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