1. Long QT Syndrome Type 3 (LQT 3) Mutations in SCN5A (Na+ Channel, I Na ) BME 301 Qaiyim Cheeseborough, Victoria Reyes, Kin Siu

2. Introduction to LQT Disorder caused by mutations in cardiac ion channels Most associated with K+ channels

3. LQT III Abnormalities in the Na+ channel Incomplete inactivation

4. Symptoms Fainting (syncope) Seizures Cardiac arrest Sudden Death

5. Diagnosis Diagnosis is preformed by analyzing the ECG readings in response to the T – wave. A autopsy may be conducted of LQT 3 syndrome through examining the SCN5A gene Normal ECG Long QT syndrome

6. Statistics 8% of all LQT carriers have SCN5A mutations Case study – found LQT-3 more lethal Onset: 50% by 12 years; 90% by 40 years Fatal arrhythmias – 39% at rest, 32% during exercise and emotional stress

7. Protein characteristics 2016 amino acids Sequence – 4 internal repeats, with 5 hydrophobic segments and 1 positively charged segment each

8. Protein Function Forms voltage- dependent, sodium selective channel Positively charged segments most likely the voltage sensors Responsible for initial upstroke in an action potential

9. Protein Mechanism for Disorder LQT III caused by incomplete inactivation III-IV linker region as blocking particle C-Terminus as a docking station Mutations at these regions can cause failure in inactivation

10. Strategy for Java simulation Change inactivation gate so that some are open at all times. Values of h and j can not be above 1

11. Same changes to h and j h_ss is the steady state value of h Change : h_ss = x + ((1.0 – x) * h_ss) X is the minimum value of h Specific changes I

12. Results Green shows normal action potential, yellow is modified version of LQT-3.

13. Sensitivity analysis

14. Conclusions Changes made resulted in action potentials similar to disorder. Mode of changes resemble mechanism of disease.

15. Web site http://www.ic.sunysb.edu/Stu/vreyes/Index.htm

16. References Neuromuscular Disease Center. ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE. 10 Feb 2000. http://medlib.med.utah.edu/kw/ecg/ecg_outline/Lesson4/#QTinterval http://www.neuro.wustl.edu/neuromuscular/mother/chan.html Bennett, P.B., Yazawa K, Makita N, George AL Jr. (1995) Molecular mechanism for an inherited cardiac arrhythmia. Nature 1995 Aug 24;376(6542):683-5 Clancy, C.E., Tateyama, M., Kass, R.S.. (2002) Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.. Clin. Invest. 110:1251-1262 ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE. http://www.neuro.wustl.edu/neuromuscular/mother/chan.html#lqt http://www.neuro.wustl.edu/neuromuscular/mother/chan.html#lqt J. Biol. Chem., Vol. 277, Issue 11, 9233-9241, March 15, 2002

17. ANY QUESTIONS ???