Letter | Published:

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

Nature Genetics volume 46, pages 6569 (2014) | Download Citation


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 proliferation1,2. PVOD is categorized into a separate pulmonary arterial hypertension–related group in the current classification of pulmonary hypertension3. PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission4. 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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We thank F. Pires, A. Dion-Minière, S. Bakas, G. Legrand and N. Raymond for technical assistance. We thank W. Carpentier for supervising SNP array experiments. We thank R. Peat for kindly editing the manuscript. D.M. and P.D. are supported by a grant from the Association Hypertension Artérielle Pulmonaire (HTAP) France. This work was supported by Programme Hospitalier de Recherche Clinique (PHRC) AOM07-041, INSERM and UPMC. The tissue bank was supported in part by the Legs Poix, Chancellerie des Universités de Paris. Bioinformatics analyses benefit from the C2BIG computing centre funded by the Région Ile de France and UPMC.

Author information


  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.

    • Mélanie Eyries
    •  & Florent Soubrier
  2. Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

    • Mélanie Eyries
    • , Anne Leroy
    • , Florence Coulet
    •  & Florent Soubrier
  3. Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.

    • Mélanie Eyries
    • , Claire Perret
    • , Florence Coulet
    • , David-Alexandre Tregouët
    •  & Florent Soubrier
  4. Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, France.

    • David Montani
    • , Barbara Girerd
    • , Olivier Sitbon
    • , Gérald Simonneau
    •  & Marc Humbert
  5. Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France.

    • David Montani
    • , Barbara Girerd
    • , Olivier Sitbon
    • , Gérald Simonneau
    •  & Marc Humbert
  6. 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.

    • David Montani
    • , Barbara Girerd
    • , Peter Dorfmüller
    • , Elie Fadel
    • , Olivier Sitbon
    • , Gérald Simonneau
    •  & Marc Humbert
  7. UMR_S 937, UPMC, INSERM, Paris, France.

    • Claire Perret
    •  & David-Alexandre Tregouët
  8. Post-Genomic Platform (P3S), UPMC, INSERM, Paris, France.

    • Christine Lonjou
    •  & Nadjim Chelghoum
  9. Cardiac Surgery Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.

    • Damien Bonnet
  10. UMR_S 765, INSERM and Université Paris Descartes, Paris, France.

    • Damien Bonnet
  11. Department of Pathology, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.

    • Peter Dorfmüller
  12. Thoracic Surgery Department, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.

    • Elie Fadel


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F.S. initiated and supervised the study. M.E., D.-A.T., M.H. and F.S. conceived and designed the experiments. D.M., B.G., D.B., O.S., G.S., E.F. and M.H. performed clinical phenotyping. D.M., B.G. and M.H. analyzed clinical data of collected patients. C.P. performed the whole-exome sequencing experiments. N.C. performed bioinformatic analyses. D.-A.T. supervised bioinformatic and biostatistical data. M.E. and F.S. analyzed whole-exome sequencing data. C.L. performed linkage analysis. A.L. performed Sanger sequencing. M.E. and F.C. analyzed Sanger sequencing data. E.F. collected lung sample specimens. P.D. performed tissue imaging. M.E., D.M., B.G., D.-A.T., M.H. and F.S. wrote the manuscript. All authors reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Florent Soubrier.

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