EIF2AK4 Mutations Cause Pulmonary Veno-occlusive Disease, a Recessive Form of Pulmonary Hypertension

Overview

Journal Nat Genet

Specialty Genetics

Date 2013 Dec 3

PMID 24292273

Citations 167

Authors

Melanie Eyries

David Montani

Barbara Girerd

Claire Perret

Anne Leroy

Christine Lonjou

Nadjim Chelghoum

Florence Coulet

Damien Bonnet

Peter Dorfmuller

Elie Fadel

Olivier Sitbon

Gerald Simonneau

David-Alexandre Tregouet

Marc Humbert

Florent Soubrier

Affiliations

Soon will be listed here.

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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References

Chan M, Nguyen P, Davis B, Ohoka N, Hayashi H, Du K . 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. 2007; 27(16):5776-89. PMC: 1952124. DOI: 10.1128/MCB.00218-07. View

Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V . Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006; 173(9):1023-30. DOI: 10.1164/rccm.200510-1668OC. View

Simonneau G, Robbins I, Beghetti M, Channick R, Delcroix M, Denton C . Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S43-S54. DOI: 10.1016/j.jacc.2009.04.012. View

Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38(16):e164. PMC: 2938201. DOI: 10.1093/nar/gkq603. View

Abecasis G, Cherny S, Cookson W, Cardon L . Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2001; 30(1):97-101. DOI: 10.1038/ng786. View

Larkin E, Newman J, Austin E, Hemnes A, Wheeler L, Robbins I . Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012; 186(9):892-6. PMC: 3530218. DOI: 10.1164/rccm.201205-0886OC. View

Eyries M, Coulet F, Girerd B, Montani D, Humbert M, LACOMBE P . ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Clin Genet. 2011; 82(2):173-9. DOI: 10.1111/j.1399-0004.2011.01727.x. View

Fessel J, Flynn C, Robinson L, Penner N, Gladson S, Kang C . Hyperoxia synergizes with mutant bone morphogenic protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension. Am J Respir Cell Mol Biol. 2013; 49(5):778-87. PMC: 3931097. DOI: 10.1165/rcmb.2012-0463OC. View

Langleben D, Heneghan J, Batten A, Wang N, Fitch N, Schlesinger R . Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988; 109(2):106-9. DOI: 10.7326/0003-4819-109-2-106. View

10.

Montani D, Price L, Dorfmuller P, Achouh L, Jais X, Yaici A . Pulmonary veno-occlusive disease. Eur Respir J. 2009; 33(1):189-200. DOI: 10.1183/09031936.00090608. View

11.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

12.

Sattlegger E, Hinnebusch A . Separate domains in GCN1 for binding protein kinase GCN2 and ribosomes are required for GCN2 activation in amino acid-starved cells. EMBO J. 2000; 19(23):6622-33. PMC: 305848. DOI: 10.1093/emboj/19.23.6622. View

13.

Anthony T, McDaniel B, Byerley R, McGrath B, Cavener D, McNurlan M . 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. 2004; 279(35):36553-61. DOI: 10.1074/jbc.M404559200. View

14.

Barrios-Rodiles M, Brown K, Ozdamar B, Bose R, Liu Z, Donovan R . High-throughput mapping of a dynamic signaling network in mammalian cells. Science. 2005; 307(5715):1621-5. DOI: 10.1126/science.1105776. View

15.

Sitbon O, Humbert M, Jais X, Ioos V, Hamid A, Provencher S . Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005; 111(23):3105-11. DOI: 10.1161/CIRCULATIONAHA.104.488486. View

16.

Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X . Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010; 181(8):851-61. DOI: 10.1164/rccm.200908-1284OC. View

17.

Machado R, Pauciulo M, Thomson J, Lane K, Morgan N, Wheeler L . BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2000; 68(1):92-102. PMC: 1234937. DOI: 10.1086/316947. View

18.

Trembath R, Thomson J, Machado R, Morgan N, Atkinson C, Winship I . Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001; 345(5):325-34. DOI: 10.1056/NEJM200108023450503. View

19.

Lantuejoul S, Sheppard M, Corrin B, Burke M, Nicholson A . Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006; 30(7):850-7. DOI: 10.1097/01.pas.0000209834.69972.e5. View

20.

Rosenthal A, VAWTER G, Wagenvoort C . Intrapulmonary veno-occlusive disease. Am J Cardiol. 1973; 31(1):78-83. DOI: 10.1016/0002-9149(73)90814-x. View