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Long QT Syndrome Type 3 (LQT 3) Mutations in SCN5A (Na+ Channel, I Na ) BME 301

Long QT Syndrome Type 3 (LQT 3) Mutations in SCN5A (Na+ Channel, I Na ) BME 301 Qaiyim Cheeseborough, Victoria Reyes, Kin Siu. Introduction to LQT. Disorder caused by mutations in cardiac ion channels Most associated with K+ channels. LQT III. Abnormalities in the Na+ channel

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Long QT Syndrome Type 3 (LQT 3) Mutations in SCN5A (Na+ Channel, I Na ) BME 301

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  1. Long QT Syndrome Type 3 (LQT 3) Mutations in SCN5A (Na+ Channel, INa) 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. Specific changes I • 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

  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 • J. Biol. Chem., Vol. 277, Issue 11, 9233-9241, March 15, 2002

  17. ANY QUESTIONS ???

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