2026-04-30T06:56:24Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/193102024-09-21T13:25:01Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Vera-Zambrano, Alba author Lago-Docampo, Mauro author Gallego, Natalia author Franco-Gonzalez, Juan Felipe author Morales-Cano, Daniel author Cruz-Utrilla, Alejandro author Villegas-Esguevillas, Marta author Fernández-Malavé, Edgar author Escribano-Subías, Pilar author Tenorio-Castaño, Jair Antonio author Perez-Vizcaino, Francisco author Valverde, Diana author González, Teresa author Cogolludo, Angel author 2023-08 Reduced expression and/or activity of Kv1.5 channels (encoded by KCNA5) is a common hallmark in human or experimental pulmonary arterial hypertension (PAH). 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. Am J Respir Cell Mol Biol. 2023 Aug;69(2):147-158. 10.1165/rcmb.2022-0245OC 1535-4989 American journal of respiratory cell and molecular biology 36917789 http://hdl.handle.net/20.500.12105/19310 Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension.