Open AccessContribution of HCN1 variant to sinus bradycardia: A case report
Author(s) -
Yu Hangang,
Gall Bryan,
Newman Mackenzie,
Hathaway Quincy,
Brundage Kathleen,
Ammer Amanda,
Mathers Peter,
Siderovski David,
Hull Robert W.
Publication year - 2021
Publication title -
journal of arrhythmia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.463
H-Index - 21
eISSN - 1883-2148
pISSN - 1880-4276
DOI - 10.1002/joa3.12598
Subject(s) - missense mutation , sinus bradycardia , bradycardia , sick sinus syndrome , medicine , exome sequencing , mutation , patch clamp , mutant , endocrinology , microbiology and biotechnology , gene , electrophysiology , genetics , heart rate , biology , blood pressure
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 ( 72 GGG 74 , “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.