title: Genetically determined differences in sodium current characteristics modulate conduction disease severity in mice with cardiac sodium channelopathy.
abstract: Conduction slowing of the electric impulse that drives the heartbeat may evoke lethal cardiac arrhythmias. Mutations in SCN5A, which encodes the pore-forming cardiac sodium channel alpha subunit, are associated with familial arrhythmia syndromes based on conduction slowing. However, disease severity among mutation carriers is highly variable. We hypothesized that genetic modifiers underlie the variability in conduction slowing and disease severity. With the aim of identifying such modifiers, we studied the Scn5a(1798insD/+) mutation in 2 distinct mouse strains, FVB/N and 129P2. In 129P2 mice, the mutation resulted in more severe conduction slowing particularly in the right ventricle (RV) compared to FVB/N. Pan-genomic mRNA expression profiling in the 2 mouse strains uncovered a drastic reduction in mRNA encoding the sodium channel auxiliary subunit beta4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta4 protein levels in 129P2 ventricular tissue, whereas abundant beta4 protein was detected in FVB/N. Sodium current measurements in isolated myocytes from the 2 mouse strains indicated that sodium channel activation in myocytes from 129P2 mice occurred at more positive potentials compared to FVB/N. Using computer simulations, this difference in activation kinetics was predicted to explain the observed differences in conduction disease severity between the 2 strains. In conclusion, genetically determined differences in sodium current characteristics on the myocyte level modulate disease severity in cardiac sodium channelopathies. In particular, the sodium channel subunit beta4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease.
authors.affiliation: Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Room K2-110, PO Box 22700, 1100 DE Amsterdam, The Netherlands. c.a.remme@amc.uva.nl
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Remme
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: Ahmad S
authors.initials: AS
authors.lastname: Amin
authors.forename: Sandra
authors.initials: S
authors.lastname: van Brunschot
authors.forename: Leander
authors.initials: L
authors.lastname: Beekman
authors.forename: Vera H M
authors.initials: VH
authors.lastname: Deneer
authors.forename: Catherine
authors.initials: C
authors.lastname: Chevalier
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Oyama
authors.forename: Haruko
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Ronald
authors.initials: R
authors.lastname: Wilders
authors.forename: Denis
authors.initials: D
authors.lastname: Escande
authors.forename: Rémi
authors.initials: R
authors.lastname: Houlgatte
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Marieke W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D053447:Channelopathies / Q000235:genetics* / Q000503:physiopathology; D004251:DNA Transposable Elements; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger / Q000235:genetics; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
chemical_list: D004251:DNA Transposable Elements; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C497241:Scn4b protein, mouse; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit