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 Incomplete inactivation

Symptoms Fainting (syncope) Seizures Cardiac arrest Sudden Death

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

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

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

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

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

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

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

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

Sensitivity analysis

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

Web site

References Neuromuscular Disease Center. ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE. 10 Feb 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: ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE. J. Biol. Chem., Vol. 277, Issue 11, , March 15, 2002

ANY QUESTIONS ???