A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews

Avishag Laish-Farkash, Michael Glikson, Dovrat Brass, Dina Marek-Yagel, Elon Pras, Nathan Dascal, Charles Antzelevitch, Eyal Nof, Haya Reznik, Michael Eldar, David Luria

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Novel HCN4 Mutation. Objectives: To conduct a clinical, genetic, and functional analysis of 3 unrelated families with familial sinus bradycardia (FSB). Background: Mutations in the hyperpolarization-activated nucleotide-gated channel (HCN4) are known to be associated with FSB. Methods and Results: Three males of Moroccan Jewish descent were hospitalized: 1 survived an out-of-hospital cardiac arrest and 2 presented with weakness and presyncopal events. All 3 had significant sinus bradycardia, also found in other first-degree relatives, with a segregation suggesting autosomal-dominant inheritance. All had normal response to exercise and normal heart structure. Sequencing of the HCN4 gene in all patients revealed a C to T transition at nucleotide position 1,454, which resulted in an alanine to valine change (A485V) in the ion channel pore found in most of their bradycardiac relatives, but not in 150 controls. Functional expression of the mutated ion channel in Xenopus oocytes and in human embryonic kidney 293 cells revealed profoundly reduced function and synthesis of the mutant channel compared to wild-type. Conclusions: We describe a new mutation in the HCN4 gene causing symptomatic FSB in 3 unrelated individuals of similar ethnic background that may indicate unexplained FSB in this ethnic group. This profound functional defect is consistent with the symptomatic phenotype.

Original languageEnglish
Pages (from-to)1365-1372
Number of pages8
JournalJournal of Cardiovascular Electrophysiology
Volume21
Issue number12
DOIs
StatePublished - 1 Dec 2010
Externally publishedYes

Keywords

  • electrophysiology
  • genetics
  • heart rate
  • ion channel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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