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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 Silvia Castillo, Qaiyim Cheeseborough, Victoria Reyes, Kin Siu. Introduction to LQT. Disorder caused by mutations in cardiac ion channels Most associated with K+ channels. Symptoms. Fainting (syncope)

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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 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

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

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

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

  13. Drug Treatment - 3 • Flecainide • 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 ???

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