Group 3 : PAH/PVOD predisposing genes & signaling

David Montani

The mechanisms responsible for the development of PAH remain mysterious despite the profusion of studies identifying, most often thanks to a prioriapproaches, a large number of puzzle pieces that we are struggling to assemble. Conversely, whole genome genetic approaches have been successful in discovering unexpected actors without a prioriassumptions, such as the BMPRII and GCN2 signaling pathways, which are highly relevant in the pathophysiology of PAH and PAH with overt features of venous/capillaries (PVOD/PCH) involvement respectively.


Currently, mutations and rare sequence variations associated with the development of PAH have been identified in more than fifteen genes (BMPR2, ALK1, BMPR1B, BMP9, CAV1, EIF2AK4, ENG, KCNK3, KCNA5, KLF2, SMAD1, SMAD4, SMAD9, TBX4, NF1, KDR, ATP13A3, AQP1 andSOX17). However, heterozygous mutations in the BMPR2gene remain the main cause of PAH in 75% of familial PAHs and 25% of sporadic PAHs, while biallelic mutations of EIF2AK4(coding for GCN2) have been identified in 100% of familial forms of PVOD and approximately 10% of sporadic MVO followed in the French PH network.


By capitalizing on a large cohort of very well characterized patients, our center is very involved in the clinical characterization of these rare patients and in the identification of new genetic factors such as GCN2/EIF2AK4, TBX4, NF1or KDR. We also have a large cohort of "healthy" carriers allowing us to study the mechanisms of incomplete penetrance of PAH-associated mutations.


Thanks to a combination of in vitrostudies on human cells (pulmonary vascular cells - endothelial and smooth muscle cells, or fibroblasts and circulating cells - PBMC), in situstudies on PAH and non-PAH lung samples and in vivostudies in relevant models of genetic predispositions that we have developed as mutant rat lines for Bmpr2or Gcn2/Eif2ak4, as well as in classic models of pulmonary hypertension (PH) (Exposure to monocrotaline, to chronic hypoxia etc), we have been able to show that the affected pathways in heritable forms of PAH are also altered in non-heritable forms. These transgenic models of PAH predisposition are also an opportunity to study the mechanisms at work in early and asymptomatic phases of the pulmonary vascular and cardiac remodeling.



  • Identify new PH susceptibility genes via a national and international network of teams dedicated to the genetics of PAH
  • Provide the community with the clinical phenotype of mutation carrier patients and understand the molecular and environmental factors responsible for the incomplete penetrance of these mutations
  • Understand the pathophysiological mechanisms at work in these inheritable forms of PAH and understand by analogy the non-heritable forms of PAH.
  • Target the altered signaling pathways in heritable and non-heritable forms of PAH to design tomorrow's breakthrough therapies