RT Journal Article
T1 A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family
A1 Cámara Checa, Anabel
A1 Perin, Francesca
A1 Rubio Alarcón, Marcos
A1 Dago, María
A1 Crespo García, Teresa
A1 Rapún, Josu
A1 Marín, María
A1 Cebrián, Jorge
A1 Gómez García, Ricardo
A1 Bermúdez Jiménez, Francisco
A1 Montserrat, Lorenzo
A1 Tamargo Menéndez, Juan
A1 Caballero Collado, Ricardo
A1 Jiménez Jáimez, Juan
A1 Delpón Mosquera, María Eva
AB AbstractIn 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.
PB National Academy of Sciences
YR 2023
FD 2023-12-05
LK https://hdl.handle.net/20.500.14352/119729
UL https://hdl.handle.net/20.500.14352/119729
LA eng
NO A. Cámara-Checa, F. Perin, M. Rubio-Alarcón, M. Dago, T. Crespo-García, J. Rapún, M. Marín, J. Cebrián, R. Gómez, F. Bermúdez-Jiménez, L. Monserrat, J. Tamargo, R. Caballero, J. Jiménez-Jáimez, & E. Delpón, A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family, Proc. Natl. Acad. Sci. U.S.A. 120 (49) e2305135120, https://doi.org/10.1073/pnas.2305135120 (2023).
NO Ministerio de Ciencia e Innovación
NO Comunidad Autónoma de Madrid
NO Instituto de Salud Carlos III
DS Docta Complutense
RD 7 jun 2025