As such, decreased expression of an important 2-hydroxyestrogen (2-OHE) catalyst, CYP1B1, may be a second-hit favouring PAH development in female HPAH patients.143 In blood isolated lymphoblastoid cells, this enzyme showed a 10-fold decreased expression in affected compared to unaffected female BMPR2 mutation carriers.143 As a follow-up, Austin et al.144 showed that female BMPR2 mutation carriers have a 4-fold decreased disease penetrance when expressing the N453S CYP1B1 variant compared to wild-type. Here, BMPR2 is linked to heritable pulmonary arterial hypertension.