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

Nature Genetics volume 46, pages 65–69 (2014)Cite this article

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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 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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Figure 1: Pathology of heritable PVOD.
Figure 2: Location of the EIF2AK4 mutations detected in patients with PVOD.
Figure 3: Immunohistochemical staining with an EIF2AK4 antibody in lungs from a control patient, a patient with PVOD not carrying mutations and a patient with PVOD who is homozygous for a EIF2AK4 mutation encoding p.Leu190Glufs*8.

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References

  1. Mandel, J., Mark, E.J. & Hales, C.A. Pulmonary veno-occlusive disease. Am. J. Respir. Crit. Care Med. 162, 1964–1973 (2000).

    Article  CAS  Google Scholar 

  2. Montani, D. et al. Pulmonary veno-occlusive disease. Eur. Respir. J. 33, 189–200 (2009).

    Article  CAS  Google Scholar 

  3. Simonneau, G. et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S43–S54 (2009).

    Article  Google Scholar 

  4. Davies, P. & Reid, L. Pulmonary veno-occlusive disease in siblings: case reports and morphometric study. Hum. Pathol. 13, 911–915 (1982).

    Article  CAS  Google Scholar 

  5. Heath, D., Segel, N. & Bishop, J. Pulmonary veno-occlusive disease. Circulation 34, 242–248 (1966).

    Article  CAS  Google Scholar 

  6. Montani, D. et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine 87, 220–233 (2008).

    Article  Google Scholar 

  7. Trembath, R.C. et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med. 345, 325–334 (2001).

    Article  CAS  Google Scholar 

  8. Girerd, B. et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am. J. Respir. Crit. Care Med. 181, 851–861 (2010).

    Article  CAS  Google Scholar 

  9. Machado, R.D. et al. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S32–S42 (2009).

    Article  CAS  Google Scholar 

  10. Rosenthal, A., Vawter, G. & Wagenvoort, C.A. Intrapulmonary veno-occlusive disease. Am. J. Cardiol. 31, 78–83 (1973).

    Article  CAS  Google Scholar 

  11. Voordes, C.G., Kuipers, J.R. & Elema, J.D. Familial pulmonary veno-occlusive disease: a case report. Thorax 32, 763–766 (1977).

    Article  CAS  Google Scholar 

  12. Larkin, E.K. et al. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 186, 892–896 (2012).

    Article  Google Scholar 

  13. Humbert, M. et al. Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis. Am. J. Respir. Crit. Care Med. 157, 1681–1685 (1998).

    Article  CAS  Google Scholar 

  14. Langleben, D. et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann. Intern. Med. 109, 106–109 (1988).

    Article  CAS  Google Scholar 

  15. Lantuéjoul, S., Sheppard, M.N., Corrin, B., Burke, M.M. & Nicholson, A.G. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am. J. Surg. Pathol. 30, 850–857 (2006).

    Article  Google Scholar 

  16. Donnelly, N., Gorman, A.M., Gupta, S. & Samali, A. The eIF2α kinases: their structures and functions. Cell. Mol. Life Sci. 70, 3493–3511 (2013).

    Article  CAS  Google Scholar 

  17. Anthony, T.G. et al. Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J. Biol. Chem. 279, 36553–36561 (2004).

    Article  CAS  Google Scholar 

  18. Chaveroux, C. et al. Identification of GCN2 as new redox regulator for oxidative stress prevention in vivo. Biochem. Biophys. Res. Commun. 415, 120–124 (2011).

    Article  CAS  Google Scholar 

  19. Fessel, J.P. et al. Hyperoxia synergizes with mutant BMPR2 to cause metabolic stress, oxidant injury, and pulmonary hypertension. Am. J. Respir. Cell Mol. Biol. 49, 778–787 (2013).

    Article  CAS  Google Scholar 

  20. Machado, R.D. et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am. J. Hum. Genet. 68, 92–102 (2001).

    Article  CAS  Google Scholar 

  21. Barrios-Rodiles, M. et al. High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307, 1621–1625 (2005).

    Article  CAS  Google Scholar 

  22. Carraro, V. et al. Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2α/ATF4 pathway. PLoS ONE 5, e15716 (2010).

    Article  CAS  Google Scholar 

  23. Chan, M.C. et al. A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor. Mol. Cell. Biol. 27, 5776–5789 (2007).

    Article  CAS  Google Scholar 

  24. Davies, R.J. et al. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L604–L615 (2012).

    Article  CAS  Google Scholar 

  25. Sattlegger, E. & Hinnebusch, A.G. Separate domains in GCN1 for binding protein kinase GCN2 and ribosomes are required for GCN2 activation in amino acid–starved cells. EMBO J. 19, 6622–6633 (2000).

    Article  CAS  Google Scholar 

  26. Humbert, M. et al. Pulmonary arterial hypertension in France: results from a national registry. Am. J. Respir. Crit. Care Med. 173, 1023–1030 (2006).

    Article  Google Scholar 

  27. Sitbon, O. et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111, 3105–3111 (2005).

    Article  CAS  Google Scholar 

  28. Sztrymf, B. et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am. J. Respir. Crit. Care Med. 177, 1377–1383 (2008).

    Article  CAS  Google Scholar 

  29. Eyries, M. et al. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Clin. Genet. 82, 173–179 (2012).

    Article  CAS  Google Scholar 

  30. O'Connell, J.R. & Weeks, D.E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet. 63, 259–266 (1998).

    Article  CAS  Google Scholar 

  31. Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    Article  CAS  Google Scholar 

  32. Kong, A. & Cox, N.J. Allele-sharing models: LOD scores and accurate linkage tests. Am. J. Hum. Genet. 61, 1179–1188 (1997).

    Article  CAS  Google Scholar 

  33. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  34. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  35. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  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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  1. Mélanie Eyries
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Contributions

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.

Corresponding author

Correspondence to Florent Soubrier.

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The authors declare no competing financial interests.

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Eyries, M., Montani, D., Girerd, B. et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 46, 65–69 (2014). https://doi.org/10.1038/ng.2844

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