Striking In Vivo Phenotype of a Disease-Associated Human SCN5A Mutation Producing Minimal Changes in VitroClinical Perspective by Hiroshi Watanabe, Tao.

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Striking In Vivo Phenotype of a Disease-Associated Human SCN5A Mutation Producing Minimal Changes in VitroClinical Perspective by Hiroshi Watanabe, Tao Yang, Dina Myers Stroud, John S. Lowe, Louise Harris, Thomas C. Atack, Dao W. Wang, Susan B. Hipkens, Brenda Leake, Lynn Hall, Sabina Kupershmidt, Nagesh Chopra, Mark A. Magnuson, Naohito Tanabe, Björn C. Knollmann, Alfred L. George, and Dan M. Roden Circulation Volume 124(9):1001-1011 August 30, 2011 Copyright © American Heart Association, Inc. All rights reserved.

D1275N SCN5A mutation in a patient with sinus node dysfunction, atrial flutter, and conduction disease. D1275N SCN5A mutation in a patient with sinus node dysfunction, atrial flutter, and conduction disease. A, Pedigree. The proband is indicated by the arrow. Individuals carrying the mutation are indicated (+). Individuals who tested negative for the mutation are indicated (−). Filled symbols indicate phenotype positive. B, Electrocardiogram and rhythm strips in the proband. C, Heterozygous single-nucleotide change in SCN5A (c.3823G|adA) resulting in p.D1275N. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.

Electrocardiography in mice. Electrocardiography in mice. A, Representative ECG traces in lead I at 3 weeks. B, Representative signal-averaged ECG traces in leads I (black) and II (gray) at 3 weeks. See Table 1 for detailed results. C, Arrhythmias recorded in DN/DN mice at 12 weeks. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.

Dilated cardiomyopathy phenotype. Dilated cardiomyopathy phenotype. A, Representative echocardiograms showing prominent increased end-systolic dimensions in DN/H and DN/DN mice at 12 weeks. See Table 2 for summary results. B, Masson trichrome staining in mice hearts. Scale bars indicate 1 mm. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.

Wild-type and D1275N sodium current in Chinese hamster ovary cells (A through C) and tsA201 cells (D through F). Wild-type and D1275N sodium current in Chinese hamster ovary cells (A through C) and tsA201 cells (D through F). Wild-type or D1275N channels were coexpressed with β1 subunits in tsA201 cells. A and D, Representative current traces. See Table 3 for summary results. B and E, Current voltage relationships. C and F, Voltage dependence of activation and inactivation. The pulse protocols are shown in the inset. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.

Sodium current in male ventricular cardiomyocytes at 3 weeks showing altered sodium channel function by the DN allele. Sodium current in male ventricular cardiomyocytes at 3 weeks showing altered sodium channel function by the DN allele. A, Representative current traces in H/H, DN/H, and DN/DN cells. See Table 3 for summary results. B, Current voltage relationships. C, Late sodium current at −30 mV. Late current amplitude was normalized to peak current amplitude. D, Voltage dependence of activation and inactivation. E and F, Inactivation time constant (τ) at −30 mV. *P<0.001 vs H/H; †P<0.001 vs DN/H. n Indicates the number of cardiomyocytes from 3 mice. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.

Action potential in male ventricular cardiomyocytes at 3 weeks. Action potential in male ventricular cardiomyocytes at 3 weeks. A, Representative action potential traces. B, Action potential duration at 50% and 90% repolarization. C, Action potential amplitude. *P<0.05 vs H/H; †P<0.01 vs H/H; ‡P<0.01 vs DN/H. n Indicates the number of cardiomyocytes from 3 mice. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.

Sodium channel expression levels at 3 weeks. Sodium channel expression levels at 3 weeks. A, Representative Western blots in ventricles. B, Sodium channel expression levels normalized to those of H/H. Calnexin was used as the loading control. C, Relative expression levels of SCN5A transcript normalized to those of β-actin in ventricle. *P<0.05 vs H/H. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.

Immunostaining for sodium channel (Nav1.5) at 3 weeks. Immunostaining for sodium channel (Nav1.5) at 3 weeks. Heart sections from the ventricles were stained with anti–Nav1.5 (green). Note the obvious lateral staining in the H/H heart and its absence in the DN/DN heart. Hiroshi Watanabe et al. Circulation. 2011;124:1001-1011 Copyright © American Heart Association, Inc. All rights reserved.