2026-05-30T08:26:47Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/192762024-09-21T09:22:47Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Cámara-Checa, Anabel author Perin, Francesca author Rubio-Alarcón, Marcos author Dago, María author Crespo-García, Teresa author Rapún, Josu author Marín, María author Cebrián, Jorge author Gómez, Ricardo author Bermúdez-Jiménez, Francisco author Monserrat, Lorenzo author Tamargo, Juan author Caballero, Ricardo author Jiménez-Jáimez, Juan author Delpón, Eva author 2023-12-05 In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state. Proc Natl Acad Sci USA. 2023 Dec 5;120(49):e2305135120. 10.1073/pnas.2305135120 1091-6490 Proceedings of the National Academy of Sciences of the United States of America 38032931 http://hdl.handle.net/20.500.12105/19276 A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.