EIF2AK4 (GCN2) mutations cause pulmonary veno-occlusive disease, a severe form of pulmonary hypertension. F. SOUBRIER1, 2, 3, M. EYRIES1,2, 3, D. MONTANI4,5, 6, B. GIRERD4,5, 6, C. PERRET1, 3, A. LEROY2, C. LONJOU7, N. CHELGHOUM7, F. COULET2, 3, D. BONNET8,9, P. DORFMULLER6,10, E. FADEL6,11, O. SITBON4, 5, 6, G. SIMONNEAU4,5,6, D.-A. TREGOUET1,3, M. HUMBERT4-6 1) UMR_S1166 UPMC and INSERM Paris France; 2) Genetics Department, Hôpital Pitié-Salpêtrière, APHP, Paris; 3) Institute for Cardiometabolism and nutrition (ICAN), Paris, France; 4) Université Pairs Sud, le Kremilin-Bicêtre, PAris France; 5) DHU Thorax innovation (TORINO), service de Pneumologie, Hôpital Bicêtre APHP, Le Kremlin-Bistre, France; 6) UMR_S 999 Labex LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France; 7) Post-Genomic Platform (P3S) UPMC; INSERM, Paris, France; 8) Pediatric Cardiology Dept, Hôpital Necker-Enfants malades, APHP, Paris, France; 9) UMR_S 765 INSERM; Université Paris-Descartes, Paris, France; 10) Dept of Pathology, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France; 11) Thoracic Surgery Dept, Centre chirurgical Marie-Lannelongue, Le Plessis Robinson, France.
Pulmonary veno-occlusive disease (PVOD) is a rare and severe cause of pulmonary hypertension characterized histologically by widespread thickening and fibrous intimal proliferation of septal veins and preseptal venules. These lesions are frequently associated with pulmonary capillary dilatation and proliferation. PVOD presents either sporadically or as familial cases. In the French referral centre for severe pulmonary hypertension, we have identified 13 PVOD families: 5 with a confirmed diagnosis based on histological studies and 8 with a highly likely diagnosis, based on clinical, functional, and radiological criteria. All PVOD families were characterized by the presence of at least two affected siblings and unaffected parents, suggesting an autosomal recessive transmission. We used a whole-exome sequencing approach and detected recessive mutations (homozygous or compound heterozygous) in the EIF2AK4 (GCN2) gene that co-segregated with PVOD in all 5 families initially studied. We subsequently identified mutations in the 8 additional PVOD families. We also found bi-allelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic PVOD cases. All identified mutations disrupted the function of the gene. In conclusion, we identified the first gene responsible for PVOD. Biallelic mutations in EIF2AK4 gene were found in 100% of familial cases and in 25% of sporadic cases of PVOD, making this new gene a major player linked to PVOD development. This discovery significantly contributes towards understanding the complex genetic architecture of pulmonary hypertension. Results obtained in the mouse model of EIF2AK4 inactivation will be presented.