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

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

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

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

5. Genetic Picture of SCN5A Located on human 3p21 chromosome Encodes alpha subunit of cardiac sodium channel protein

6. Specific Mutations 17 known mutations, 14 are single nucleotide Codon Location Nucleotide Amino acid 1623CGA->CAAArg->Gln 1644CGC->CACArg->His 1777GTG->ATGVal->Met

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

8. 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 Poorly understood III-IV linker region as blocking particle C-Terminus as a docking station Mutations at these regions can cause failure in inactivation

10. Fraction of Na+ channels fail to inactivate Cause sustained Na+ ion influx Leads to longer QT-intervals in an electrocardiogram Mechanism for Disorder

11. Drug Treatment - 1 Lidocaine Most commonly used Most commonly used Inhibits the influx of sodium Inhibits the influx of sodium

12. Mexiletine Orally administered Orally administered Mechanism similar to Lidocaine Mechanism similar to Lidocaine Drug Treatment - 2

13. Drug Treatment - 3 Flecainide Mechanism similar to Lidocaine Mechanism similar to Lidocaine

14. Risk Factors History of syncope Duration of episode and QT interval Congenital deafness Male children Female pregnancy cardiac events are common

15. 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

16. References Neuromuscular Disease Center. ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE. 10 Feb 2000. http://www.neuro.wustl.edu/neuromuscular/mother/chan.html

17. ANY QUESTIONS ???