A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.

1. CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain.
Authors
Tenorio J^{1,

6}
Fernández L^{1,

6}
Nevado J^{1,

6}
Arias P^{1,

6}
Heath K^{1,

6}
Lapunzina P^{1,

6}
(6 authors)
2. RIC (Red de Investigación Cardiovascular), ISCIII, 28029 Madrid, Spain.
Authors
Navas P^{2,

4}
Escribano-Subías P^{2,

4}
(2 authors)
3. Unidad de Cardiología pediátrica, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Authors
Barrios E³
(1 author)
4. Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología. Hospital Doce de Octubre, Madrid, Spain.
Authors
Navas P^{2,

4}
Quezada CA⁴
Escribano-Subías P^{2,

4}
(3 authors)
5. Servicio de Neumología, Hospital Universitario Vall d' Hebron, Barcelona, Spain.
Authors
López-Meseguer M⁵
(1 author)

Show all (8)

ORCIDs linked to this article

Show all (9)

Clinical Genetics, 07 Jan 2015, 88(6):579-583
https://doi.org/10.1111/cge.12549 PMID: 25512148

Abstract

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.

Full text links

Read article at publisher's site: https://doi.org/10.1111/cge.12549

References

Articles referenced by this article (23)

Updated clinical classification of pulmonary hypertension.
Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R
J Am Coll Cardiol, (1 Suppl):S43-S54 2009
MED: 19555858
Updated clinical classification of pulmonary hypertension.
Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R
J Am Coll Cardiol, (25 Suppl):D34-41 2013
MED: 24355639
Molecular mechanisms of pulmonary arterial remodeling.
Crosswhite P, Sun Z
Mol Med, 191-201 2014
MED: 24676136
State of the art: advanced imaging of the right ventricle and pulmonary circulation in humans (2013 Grover Conference series).
van de Veerdonk MC, Marcus JT, Bogaard HJ, Vonk Noordegraaf A
Pulm Circ, (2):158-168 2014
MED: 25006434
Heritable forms of pulmonary arterial hypertension.
Austin ED, Loyd JE
Semin Respir Crit Care Med, (5):568-580 2013
MED: 24037626
Mutations in the human TBX4 gene cause small patella syndrome.
Bongers EM, Duijf PH, van Beersum SE, Schoots J, Van Kampen A, Burckhardt A, Hamel BC, Losan F, Hoefsloot LH, Yntema HG, Knoers NV, van Bokhoven H
Am J Hum Genet, (6):1239-1248 2004
MED: 15106123
EIF2AK4 mutations in pulmonary capillary hemangiomatosis.
Best DH, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, Rosenzweig EB, Bayrak-Toydemir P, Mao R, Cahill BC, Tazelaar HD, Leslie KO, Hemnes AR, Robbins IM, Elliott CG
Chest, (2):231-236 2014
MED: 24135949
EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension.
Eyries M, Montani D, Girerd B, Perret C, Leroy A, Lonjou C, Chelghoum N, Coulet F, Bonnet D, Dorfmuller P, Fadel E, Sitbon O, Simonneau G, Tregouet DA, Humbert M, Soubrier F
Nat Genet, (1):65-69 2013
MED: 24292273
Genetic studies of the Roma (Gypsies): a review.
Kalaydjieva L, Gresham D, Calafell F
BMC Med Genet, 5 2001
MED: 11299048
Prevalence of congenital anomaly syndromes in a Spanish gypsy population.
Martinez-Frias ML, Bermejo E
J Med Genet, (7):483-486 1992
MED: 1640427

Show 10 more references (10 of 23)

Citations & impact

Impact metrics

Citations

Jump to Citations

Data citations

Jump to Data

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/10990818

Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/10990818

Smart citations by scite.ai
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.1111/cge.12549

Supporting

Mentioning

Contrasting

Article citations

Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.
Emanuelli G, Zhu J, Li W, Morrell NW, Marciniak SJ
Hum Mol Genet, 33(17):1495-1505, 01 Aug 2024
Cited by: 2 articles | PMID: 38776952 | PMCID: PMC11336063
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC
Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.
Welch CL, Aldred MA, Balachandar S, Dooijes D, Eichstaedt CA, Gräf S, Houweling AC, Machado RD, Pandya D, Prapa M, Shaukat M, Southgate L, Tenorio-Castano J, ClinGen PH VCEP, Chung WK, International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI)
Genet Med, 25(11):100925, 05 Jul 2023
Cited by: 12 articles | PMID: 37422716 | PMCID: PMC10766870
Free full text in Europe PMC
Genetic counselling and testing in pulmonary arterial hypertension: a consensus statement on behalf of the International Consortium for Genetic Studies in PAH.
Eichstaedt CA, Belge C, Chung WK, Gräf S, Grünig E, Montani D, Quarck R, Tenorio-Castano JA, Soubrier F, Trembath RC, Morrell NW, for PAH-ICON associated with the PVRI
Eur Respir J, 61(2):2201471, 23 Feb 2023
Cited by: 11 articles | PMID: 36302552 | PMCID: PMC9947314
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC
Transcriptomic Study on the Lungs of Broilers with Ascites Syndrome.
Guo D, Zhang J, Han Y, Cui L, Wang H, Wang K, Li P, Deng R, Kang J, Duan Z
Animals (Basel), 13(1):175, 02 Jan 2023
Cited by: 1 article | PMID: 36611783 | PMCID: PMC9817706
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC
Pulmonary veno-occlusive disease in Sjogren's syndrome: a case report.
Zeng X, Liu Q, Rathinasabapathy A, Zha L, Liu D, Tang Y, Sun J, Luo H, Yu Z
BMC Pulm Med, 23(1):26, 18 Jan 2023
Cited by: 0 articles | PMID: 36653758 | PMCID: PMC9847112
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Go to all (30) article citations

Data

Data that cites the article

This data has been provided by curated databases and other sources that have cited the article.

Proteins in UniProt

eIF-2-alpha kinase GCN2(UniProt - Q9P2K8)

The Rat Genome Database (RGD) was established in 1999 and rapidly became the premier site for genetic, genomic, phenotype, and disease-related data generated from rat research. In addition, RGD has expanded to include a large body of structured and standardized data for eight species (rat, mouse, human, chinchilla, bonobo, 13-lined ground squirrel, dog and pig). Much of this data is the result of manual curation work by RGD curators. In other instances, it has been imported into RGD from other databases through custom ELT (Extract, Load and Transform) pipelines giving RGD users integrated access to a wide variety of data to support their research efforts. RGD also offers a growing suite of innovative tools for querying, analyzing and visualizing this data making it a valuable resource for researchers worldwide.

Search life-sciences literature (45,103,589 articles, preprints and more)

A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.

Author information

Affiliations

Authors

Authors

Authors

Authors

Authors

ORCIDs linked to this article

Abstract

Full text links

References

Citations & impact

Impact metrics

Citations of article over time

Alternative metrics

Article citations

Data

Data that cites the article

Proteins in UniProt

Similar Articles

Funding

ACTELION

“Spanish Pulmonary Hypertension National Association” (ANHP)

Partnerships & funding