title: A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.
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.
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain, Universidad Autónoma de Madrid (UAM), 28046 Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tenorio
authors.affiliation: RIC (Red de Investigación Cardiovascular), ISCIII, 28029 Madrid, Spain.|Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología. Hospital Doce de Octubre, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Navas
authors.affiliation: Unidad de Cardiología pediátrica, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Barrios
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain, Universidad Autónoma de Madrid (UAM), 28046 Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Fernández
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain, Universidad Autónoma de Madrid (UAM), 28046 Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Nevado
authors.affiliation: Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología. Hospital Doce de Octubre, Madrid, Spain.
authors.forename: C A
authors.initials: CA
authors.lastname: Quezada
authors.affiliation: Servicio de Neumología, Hospital Universitario Vall d' Hebron, Barcelona, Spain.|Universitat Autònoma de Barcelona, Barcelonal, Spain.|CIBERES, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, ISCIII, 28029 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: López-Meseguer
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain, Universidad Autónoma de Madrid (UAM), 28046 Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Arias
authors.affiliation: INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain, Universidad Autónoma de Madrid (UAM), 28046 Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Mena
authors.affiliation: Servicio de Neumología, Hospital Txagorritxu, Vitoria, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Lobo
authors.affiliation: Servicio de Neumología, Hospital Central de Asturias, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Alvarez
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain, Universidad Autónoma de Madrid (UAM), 28046 Madrid, Spain.
authors.forename: K
authors.initials: K
authors.lastname: Heath
authors.affiliation: RIC (Red de Investigación Cardiovascular), ISCIII, 28029 Madrid, Spain.|Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología. Hospital Doce de Octubre, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Escribano-Subías
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain, Universidad Autónoma de Madrid (UAM), 28046 Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Lapunzina
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D065627:Familial Primary Pulmonary Hypertension / Q000208:ethnology / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011174:Portugal; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D006178:Romani People / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013030:Spain
chemical_list: C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: EIF2AK4; Gypsies; SNP-arrays; autosomal recessive disease; c.3344C>T; pulmonary arterial hypertension