title: An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by a high genetic heterogeneity with several related genes recently described, including BMPR2,TBX4 and KCNK3. The association between KCNK3 and PAH has been recently identified, but the prognosis and phenotype associated with these mutations have been poorly described. We studied a series of 136 idiopathic and hereditary PAH Spanish patients for BMPR2, TBX4 and KCNK3 mutations. We report the results of KCNK3 in which we were able to describe two new mutations (p.Gly106Arg and p.Leu214Arg) in three patients. The first one was found in a patient belonging to a consanguineous Romani family, who carried a homozygous mutation in KCNK3 and developed a severe and early form of the disease. To the best of our knowledge, this is the first time that a homozygous mutation in KCNK3 is reported in a PAH patient. The second one was found in a patient who presented at the young adult age a severe form of the disease. The present report supports the contribution of KCNK3 mutations to the genetic etiology of PAH and strongly suggests that mutations in KCNK3 follow incomplete dominance with worsening of the clinical features in homozygous patients.
authors.affiliation: Servicio de Cardiología, Hospital Universitario Gregorio Marañón, Madrid, Spain.|Red de Investigación Cardiovascular (RIC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Navas Tejedor
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tenorio Castaño
authors.affiliation: Unidad de Cardiopatías Familiares. Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Palomino Doza
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Arias Lajara
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Gordo Trujillo
authors.affiliation: Servicio de Neumología, Hospital Universitario Vall d'Hebrón, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: López Meseguer
authors.affiliation: Servicio de Neumología, Hospital Universitario Vall d'Hebrón, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Román Broto
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Lapunzina Abadía
authors.affiliation: Red de Investigación Cardiovascular (RIC), Instituto de Salud Carlos III (ISCIII), 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 Subía
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3
keywords: KCNK3; hereditary pulmonary arterial hypertension; idiopathic pulmonary arterial hypertension; incomplete dominance; screening