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


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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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



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.

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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).

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