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(Circulation Research. 2009;104:1283.)
© 2009 American Heart Association, Inc.

Cellular Biology

Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy

Carol Ann Remme, Brendon P. Scicluna, Arie O. Verkerk, Ahmad S. Amin, Sandra van Brunschot, Leander Beekman, Vera H.M. Deneer, Catherine Chevalier, Fumitaka Oyama, Haruko Miyazaki, Nobuyuki Nukina, Ronald Wilders, Denis Escande, Rémi Houlgatte, Arthur A.M. Wilde, Hanno L. Tan, Marieke W. Veldkamp, Jacques M.T. de Bakker, Connie R. Bezzina

From the Heart Failure Research Center (C.A.R., B.P.S., A.O.V., A.S.A., S.v.B., L.B., R.W., A.A.M.W., H.L.T., M.W.V., J.M.T.d.B., C.R.B.), Academic Medical Center, University of Amsterdam, The Netherlands; Department of Clinical Pharmacy (V.H.M.D.), St Antonius Hospital, Nieuwegein, The Netherlands; Université de Nantes, Faculté de Médecine (C.C., D.E., R.H.), l’institut du thorax; and INSERM U533 (C.C., D.E., R.H.), Nantes, France; Laboratory for Structural Neuropathology (F.O., H.M., N.N.), RIKEN Brain Science Institute, Saitama, Japan; Centre Hospitalier Universitaire Nantes (D.E., R.H.), l’institut du thorax, France; and Interuniversity Cardiology Institute of The Netherlands (J.M.T.d.B.), Utrecht, The Netherlands.

Correspondence to C.A. Remme, MD, PhD, Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, Room K2-110, PO Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail c.a.remme{at}amc.uva.nl

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 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 β4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable β4 protein levels in 129P2 ventricular tissue, whereas abundant β4 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 β4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease.

Key Words: genetics • gene expression • sodium channels • conduction • mouse mutants

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