TY - JOUR
T1 - A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews
AU - Laish-Farkash, Avishag
AU - Glikson, Michael
AU - Brass, Dovrat
AU - Marek-Yagel, Dina
AU - Pras, Elon
AU - Dascal, Nathan
AU - Antzelevitch, Charles
AU - Nof, Eyal
AU - Reznik, Haya
AU - Eldar, Michael
AU - Luria, David
PY - 2010/12/1
Y1 - 2010/12/1
N2 - 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.
AB - 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.
KW - electrophysiology
KW - genetics
KW - heart rate
KW - ion channel
UR - http://www.scopus.com/inward/record.url?scp=78650153150&partnerID=8YFLogxK
U2 - 10.1111/j.1540-8167.2010.01844.x
DO - 10.1111/j.1540-8167.2010.01844.x
M3 - Article
C2 - 20662977
AN - SCOPUS:78650153150
SN - 1045-3873
VL - 21
SP - 1365
EP - 1372
JO - Journal of Cardiovascular Electrophysiology
JF - Journal of Cardiovascular Electrophysiology
IS - 12
ER -