@article{25c2289eeb644b3c833d2933a022b9fe,
title = "Contribution of HCN1 variant to sinus bradycardia: A case report",
abstract = "Background: Missense mutations in the hyperpolarization-activated cyclic nucleotide-modulated (HCN) channel 4 (HCN4) are one of the genetic causes of cardiac sinus bradycardia. Objective: To investigate possible HCN4 channel mutation in a young patient with profound sinus bradycardia. Methods: Direct sequencing of HCN4 and whole-exome sequencing were performed on DNA samples from the indexed patient (P), the patient's son (PS), and a family unrelated healthy long-distance running volunteer (V). Resting heart rate was 31 bpm for P, 67 bpm for PS, and 50 bpm for V. Immunoblots, flow cytometry, and immunocytofluorescence confocal imaging were used to study cellular distribution of channel variants. Patch-clamp electrophysiology was used to investigate the properties of mutant HCN1 channels. Results: In P no missense mutations were found in the HCN4 gene; instead, we found two heterozygous variants in the HCN1 gene: deletion of an N-terminal glycine triplet (72GGG74, “N-del”) and a novel missense variant, P851A, in the C-terminal region. N-del variant was found before and shared by PS. These two variations were not found in V. Compared to wild type, N-del and P851A reduced cell surface expression and negatively shifted voltage-activation with slower activation kinetics. Conclusion: Decreased channel activity HCN1 mutant channel makes it unable to contribute to early depolarization of sinus node action potential, thus likely a main cause of the profound sinus bradycardia in this patient.",
keywords = "HCN1, HCN4, hyperpolarization-activated ion channel, missense mutation, sinus bradycardia, whole-exome sequencing",
author = "Hangang Yu and Bryan Gall and Mackenzie Newman and Quincy Hathaway and Kathleen Brundage and Amanda Ammer and Peter Mathers and David Siderovski and Hull, {Robert W.}",
note = "Funding Information: This work has been supported by American Heart Association Grant-in-Aid (13GRNT16420018), National Institute of General Medical Sciences of the National Institutes of Health (U54GM104942), and a Research Development Grant from Health Sciences Center of West Virginia University to HY. The WVU Flow Cytometry & Single Cell Core Facility is supported by the WV IDeA grants P20GM121322 (CoBRE) and P20GM103434 (WV INBRE) and the S10 0D016265 (LSR Fortessa). Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number U54GM104942. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). The human version of wild-type HCN1 cDNA plasmid was kindly provided by Dr Juliane Stieber (Institut F{\"u}r Experimentelle Und Klinische Pharmakologie Und Toxikologie Friedrich - Alexander Universit{\"a}t Erlangen, Germany). We thank WVU Genomic Core for PCR sequencing of HCN4 gene. We are also grateful for assistance from research nurse Annina Guzek for IRB process and blood drawing. Funding Information: This work has been supported by American Heart Association Grant‐in‐Aid (13GRNT16420018), National Institute of General Medical Sciences of the National Institutes of Health (U54GM104942), and a Research Development Grant from Health Sciences Center of West Virginia University to HY. The WVU Flow Cytometry & Single Cell Core Facility is supported by the WV IDeA grants P20GM121322 (CoBRE) and P20GM103434 (WV INBRE) and the S10 0D016265 (LSR Fortessa). Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number U54GM104942. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Publisher Copyright: {\textcopyright} 2021 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society",
year = "2021",
month = oct,
doi = "10.1002/joa3.12598",
language = "English",
volume = "37",
pages = "1337--1347",
journal = "Journal of Arrhythmia",
issn = "1880-4276",
publisher = "John Wiley & Sons Inc.",
number = "5",
}