2. Academic Validation
  3. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension

EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension

  • Nat Genet. 2014 Jan;46(1):65-9. doi: 10.1038/ng.2844.
Mélanie Eyries 1,  David Montani 2,  Barbara Girerd 2,  Claire Perret 3,  Anne Leroy 4,  Christine Lonjou 5,  Nadjim Chelghoum 5,  Florence Coulet 6,  Damien Bonnet 7,  Peter Dorfmüller 8,  Elie Fadel 9,  Olivier Sitbon 2,  Gérald Simonneau 2,  David-Alexandre Tregouët 3,  Marc Humbert 2,  Florent Soubrier 1
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 1] Institute for Cardiometabolism and Nutrition (ICAN), Paris, France. [2] UMR_S 937, UPMC, INSERM, Paris, France.
  • 4 Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
  • 5 Post-Genomic Platform (P3S), UPMC, INSERM, Paris, France.
  • 6 1] Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. [2] Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
  • 7 1] Cardiac Surgery Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. [2] UMR_S 765, INSERM and Université Paris Descartes, Paris, France.
  • 8 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.
  • 9 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.
PMID: 24292273 DOI: 10.1038/ng.2844
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.

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