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Likewise, genetic variants in KCNA5 have been found in patients with PAH, but their functional consequences and potential impact on the disease are largely unknown. Herein, this study aimed to characterize the functional consequences of seven KCNA5 variants found in a cohort of patients with PAH. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with wild-type or mutant Kv1.5 cDNA. Flow cytometry, Western blot, and confocal microscopy techniques were used for measuring protein expression and cell apoptosis in HEK293 and human pulmonary artery smooth muscle cells. KCNA5 variants (namely, Arg184Pro and Gly384Arg) found in patients with PAH resulted in a clear loss of potassium channel function as assessed by electrophysiological and molecular modeling analyses. The Arg184Pro variant also resulted in a pronounced reduction of Kv1.5 expression. Transfection with Arg184Pro or Gly384Arg variants decreased apoptosis of human pulmonary artery smooth muscle cells compared with the wild-type cells, demonstrating that KCNA5 dysfunction in both variants affects cell viability. Thus, in addition to affecting channel activity, both variants were associated with impaired apoptosis, a crucial process linked to the disease. The estimated prevalence of dysfunctional KCNA5 variants in the PAH population analyzed was around 1%. The data indicate that some KCNA5 variants found in patients with PAH have critical consequences for channel function, supporting the idea that KCNA5 pathogenic variants may be a causative or contributing factor for PAH.<\/jats:p>","DOI":"10.1165\/rcmb.2022-0245oc","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T16:33:07Z","timestamp":1678811587000},"page":"147-158","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":21,"title":["Novel Loss-of-Function\n                    <i>KCNA5<\/i>\n                    Variants in Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4040-1920","authenticated-orcid":false,"given":"Alba","family":"Vera-Zambrano","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology and"},{"name":"Department of Biochemistry, School of Medicine, University Autonoma of Madrid, Madrid, Spain"},{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8799-6079","authenticated-orcid":false,"given":"Mauro","family":"Lago-Docampo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Nanomateriais e Biomedicina (CINBIO), Universidade de Vigo, Vigo, Spain"},{"name":"Rare Diseases and Pediatric Medicine, Galicia Sur Health Research Institute, SERGAS-UVIGO, Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Gallego","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics-IdiPAZ, Universitary Hospital La Paz, University Autonoma of Madrid, Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, University Hospital La Paz, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Felipe","family":"Franco-Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Structural and Chemical Biology, Margarita Salas Center for Biological Research, Scientific Research Council, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-4633","authenticated-orcid":false,"given":"Daniel","family":"Morales-Cano","sequence":"additional","affiliation":[{"name":"Experimental Pathology of Atherosclerosis Laboratory, National Center for Cardiovascular Research Carlos III, Madrid, Spain"},{"name":"Atherosclerosis Research Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3851-4037","authenticated-orcid":false,"given":"Alejandro","family":"Cruz-Utrilla","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares, and"},{"name":"Unidad Multidisciplinar de Hipertensi\u00f3n Pulmonar, Servicio de Cardiolog\u00eda, Hospital Universitario 12 de Octubre, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Villegas-Esguevillas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology and"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Respitatorias, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Madrid, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Fern\u00e1ndez-Malav\u00e9","sequence":"additional","affiliation":[{"name":"Department of Immunology, Ophthalmology and ENT, School of Medicine, University Complutense of Madrid, Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Escribano-Sub\u00edas","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares, and"},{"name":"Unidad Multidisciplinar de Hipertensi\u00f3n Pulmonar, Servicio de Cardiolog\u00eda, Hospital Universitario 12 de Octubre, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jair Antonio","family":"Tenorio-Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics-IdiPAZ, Universitary Hospital La Paz, University Autonoma of Madrid, Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, University Hospital La Paz, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6309-7418","authenticated-orcid":false,"given":"Francisco","family":"Perez-Vizcaino","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology and"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Respitatorias, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Madrid, Spain; 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