title: A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Heart Institute, Sheba Medical Center, Tel Hashomer, Israel Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Avishag
authors.initials: A
authors.lastname: Laish-Farkash
authors.forename: Michael
authors.initials: M
authors.lastname: Glikson
authors.forename: Dovrat
authors.initials: D
authors.lastname: Brass
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
authors.forename: Nathan
authors.initials: N
authors.lastname: Dascal
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Eyal
authors.initials: E
authors.lastname: Nof
authors.forename: Haya
authors.initials: H
authors.lastname: Reznik
authors.forename: Michael
authors.initials: M
authors.lastname: Eldar
authors.forename: David
authors.initials: D
authors.lastname: Luria
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001146:Arrhythmia, Sinus / Q000208:ethnology / Q000235:genetics*; D001919:Bradycardia / Q000208:ethnology / Q000235:genetics*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007585:Jews / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009018:Morocco / Q000208:ethnology; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D015221:Potassium Channels; D014982:Xenopus laevis; D055815:Young Adult
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels