Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Iron deficiency is common in IPAH patients and associated with disease severity and poor clinical outcome. Inappropriately raised hepcidin levels, which impair iron absorption from the gut, may be a factor.

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Background We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial (PA) endothelial cells (ECs) from idiopathic PA hypertension (IPAH) patients compared to controls. Since HMGA1 promotes epithelial to mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (EndMT), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced IPAH. Methods and Results We documented increased HMGA1 in PAECs cultured from IPAH vs. donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to PA endothelium, and identified many cells double-positive for HMGA1 and smooth muscle 22 alpha (SM22α) in occlusive and plexogenic lesions. Since decreased expression and function of bone morphogenetic protein receptor (BMPR)2 is observed in PAH, we reduced BMPR2 by siRNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced PECAM-1 (CD31) and increased EndMT markers, αSMA, SM22α, calponin, phospho-vimentin and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSMA was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary ECs from mice with EC-specific loss of BMPR2 showed similar gene and protein changes. Conclusions Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.