Long QT Syndrome Type 3 (LQT 3)

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

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Introduction to LQT

• Disorder caused by mutations in cardiac ion
  channels
• Most associated with K channels

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Symptoms

• Fainting (syncope)
• Seizures
• Cardiac arrest
• Sudden Death

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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
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Genetic Picture of SCN5A

• Located on human 3p21 chromosome
• Encodes alpha subunit of cardiac sodium channel
  protein

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Specific Mutations
Codon Location Nucleotide Amino acid
1623 CGA-gtCAA Arg-gtGln
1644 CGC-gtCAC Arg-gtHis
1777 GTG-gtATG Val-gtMet

• 17 known mutations, 14 are single nucleotide

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Physical Characteristics

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

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Function

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

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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

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Mechanism for Disorder

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

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Drug Treatment - 1

• Lidocaine
• Most commonly used
• Inhibits the influx of sodium

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Drug Treatment - 2

• Mexiletine
• Orally administered
• Mechanism similar to Lidocaine

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Drug Treatment - 3

• Flecainide
• Mechanism similar to Lidocaine

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Risk Factors

• History of syncope
• Duration of episode and QT interval
• Congenital deafness
• Male children
• Female pregnancy cardiac events are common

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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

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References

• Neuromuscular Disease Center. ION CHANNELS,
  TRANSMITTERS, RECEPTORS DISEASE. 10 Feb 2000.
• lt http//www.neuro.wustl.edu/neuromuscular/mo
  ther/chan.htmlgt

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ANY QUESTIONS ???