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) Seizures Cardiac arrest Sudden Death
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
Genetic Picture of SCN5A Located on human 3p21 chromosome Encodes alpha subunit of cardiac sodium channel protein
Specific Mutations 17 known mutations, 14 are single nucleotide Codon Location Nucleotide Amino acid 1623CGA->CAAArg->Gln 1644CGC->CACArg->His 1777GTG->ATGVal->Met
Physical Characteristics 2016 amino acids Sequence – 4 internal repeats, with 5 hydrophobic segments and 1 positively charged segment each
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 Poorly understood III-IV linker region as blocking particle C-Terminus as a docking station Mutations at these regions can cause failure in inactivation
Fraction of Na+ channels fail to inactivate Cause sustained Na+ ion influx Leads to longer QT-intervals in an electrocardiogram Mechanism for Disorder
Drug Treatment - 1 Lidocaine Most commonly used Most commonly used Inhibits the influx of sodium Inhibits the influx of sodium
Mexiletine Orally administered Orally administered Mechanism similar to Lidocaine Mechanism similar to Lidocaine Drug Treatment - 2
Drug Treatment - 3 Flecainide Mechanism similar to Lidocaine Mechanism similar to Lidocaine
Risk Factors History of syncope Duration of episode and QT interval Congenital deafness Male children Female pregnancy cardiac events are common
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
References Neuromuscular Disease Center. ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE. 10 Feb
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