title: EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension.
abstract: Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation. PVOD is categorized into a separate pulmonary arterial hypertension-related group in the current classification of pulmonary hypertension. PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission. Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension.
authors.affiliation: 1] Unité Mixte de Recherche en Santé (UMR_S 956), Université Pierre and Marie Curie Université Paris 06 (UPMC) and Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France. [2] Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. [3] Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Eyries
authors.affiliation: 1] Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, France. [2] Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. [3] INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.affiliation: 1] Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, France. [2] Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. [3] INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.affiliation: 1] Institute for Cardiometabolism and Nutrition (ICAN), Paris, France. [2] UMR_S 937, UPMC, INSERM, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Perret
authors.affiliation: Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Leroy
authors.affiliation: Post-Genomic Platform (P3S), UPMC, INSERM, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lonjou
authors.affiliation: Post-Genomic Platform (P3S), UPMC, INSERM, Paris, France.
authors.forename: Nadjim
authors.initials: N
authors.lastname: Chelghoum
authors.affiliation: 1] Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. [2] Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Coulet
authors.affiliation: 1] Cardiac Surgery Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. [2] UMR_S 765, INSERM and Université Paris Descartes, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: 1] INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France. [2] Department of Pathology, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.affiliation: 1] INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France. [2] Thoracic Surgery Department, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: 1] Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, France. [2] Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. [3] INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
authors.affiliation: 1] Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, France. [2] Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. [3] INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: 1] Institute for Cardiometabolism and Nutrition (ICAN), Paris, France. [2] UMR_S 937, UPMC, INSERM, Paris, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Tregouët
authors.affiliation: 1] Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, France. [2] Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. [3] INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: 1] Unité Mixte de Recherche en Santé (UMR_S 956), Université Pierre and Marie Curie Université Paris 06 (UPMC) and Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France. [2] Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. [3] Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
mesh_terms: D000328:Adult; D002874:Chromosome Mapping; D005260:Female; D006720:Homozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011668:Pulmonary Veno-Occlusive Disease / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases