The State of Biophysics - Biophysical Journal

1022

Zylla and Thomas

alteration in channel structure has on its function in the context of cardiac activity. Furthermore, mutations in genes encoding for ion channels are in certain cases associated with structural alterations of the heart muscle, which may directly affect the strength of the heart ( 22 ). These intri- cacies can be well distinguished by biophysical methods in cellular experiments, animal models, computer simula- tions, and clinical observations in patients affected by channelopathies. In summary, biophysical studies have contributed signif- icantly to the discovery and understanding of inherited ar- rhythmias. Additionally, they help to identify prospective drug targets, as well as potential risk factors for cardiac ar- rhythmias. Furthermore, because many diseases affect bio- physical properties of cells in different organs, evidence derived from biophysical studies may help patients and phy- sicians on a multidisciplinary level. After careful evaluation of the case and genetic testing, the girl and her parents are informed about the diagnosis of Jervell-Lange-Nielsen syndrome and its potential risks. She receives a low-dose beta blocker for prevention of ar- rhythmias and avoidance of strenuous exercise, particularly swimming, is recommended. Her younger brother turned out to have developed a respiratory infection, which led to the episode of loss of consciousness but, apart from that, is entirely healthy. Advice for the young swimmer: staying on the safe side (of the pool) 1. Deo, R., and C. M. Albert. 2012. Epidemiology and genetics of sudden cardiac death. Circulation. 125:620–637 . 2. Haider, A. W., M. G. Larson, . , D. Levy. 1998. Increased left ventric- ular mass and hypertrophy are associated with increased risk for sud- den death. J. Am. Coll. Cardiol. 32:1454–1459 . 3. Noseworthy, P. A., and C. Newton-Cheh. 2008. Genetic determinants of sudden cardiac death. Circulation. 118:1854–1863 . 4. Curran, M. E., I. Splawski, . , M. T. Keating. 1995. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 80:795–803 . 5. Wang, Q., M. E. Curran, . , M. T. Keating. 1996. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat. Genet. 12:17–23 . REFERENCES

6. Thomas, D., C. A. Karle, and J. Kiehn. 2006. The cardiac hERG/I Kr potassium channel as pharmacological target: structure, function, regu- lation, and clinical applications. Curr. Pharm. Des. 12:2271–2283 . 7. Aidery, P., J. Kisselbach, . , D. Thomas. 2012. Impaired ion channel function related to a common KCNQ1 mutation–implications for risk stratification in long QT syndrome 1. Gene. 511:26–33 . 8. Itzhaki, I., L. Maizels, . , L. Gepstein. 2011. Modelling the long QT syndrome with induced pluripotent stem cells. Nature. 471:225–229 . 9. Moretti, A., M. Bellin, . , K. L. Laugwitz. 2010. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363:1397–1409 . 10. Saenen, J. B., and C. J. Vrints. 2008. Molecular aspects of the congen- ital and acquired Long QT Syndrome: clinical implications. J. Mol. Cell. Cardiol. 44:633–646 . 11. Schwartz, P. J., S. G. Priori, . , R. Bloise. 2001. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life- threatening arrhythmias. Circulation. 103:89–95 . 12. Seebohm, G., N. Strutz-Seebohm, . , F. Lang. 2008. Long QT syn- drome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels. Circ. Res. 103:1451– 1457 . 13. Thomas, D., J. Kiehn, . , C. A. Karle. 2004. Adrenergic regulation of the rapid component of the cardiac delayed rectifier potassium current, I( Kr) , and the underlying hERG ion channel. Basic Res. Cardiol. 99:279–287 . 14. Thomas, D., J. Kiehn, . , C. A. Karle. 2003. Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc. Res. 60:235–241 . 15. Horner, J. M., M. M. Horner, and M. J. Ackerman. 2011. The diag- nostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm. 8:1698–1704 . 16. Wong, J. A., L. J. Gula, . , A. D. Krahn. 2010. Utility of treadmill testing in identification and genotype prediction in long-QT syndrome. Circ Arrhythm Electrophysiol. 3:120–125 . 17. Shimizu, W., and M. Horie. 2011. Phenotypic manifestations of muta- tions in genes encoding subunits of cardiac potassium channels. Circ. Res. 109:97–109 . 18. Behr, E. R., and D. Roden. 2013. Drug-induced arrhythmia: pharmaco- genomic prescribing? Eur. Heart J. 34:89–95 . 19. Martin, C. A., Y. Zhang, . , C. L. Huang. 2010. Increased right ventric- ular repolarization gradients promote arrhythmogenesis in a murine model of Brugada syndrome. J. Cardiovasc. Electrophysiol. 21:1153–1159 . 20. Benson, D. W., D. W. Wang, . , A. L. George, Jr. 2003. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J. Clin. Invest. 112:1019–1028 . 21. Lei, M., H. Zhang, . , C. L. Huang. 2007. SCN5A and sinoatrial node pacemaker function. Cardiovasc. Res. 74:356–365 . 22. Schweizer, P. A., J. Schro¨ter, . , D. Thomas. 2014. The symptom com- plex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. J. Am. Coll. Cardiol. 64:757–767 .

Biophysical Journal 110(5) 1017–1022