LQT3 is caused by a mutation that affects the inactivation gate of the cardiac sodium channel, resulting in a sustained inward sodium current. This prolongs the cardiac action potential and QT interval. Symptoms include arrhythmia and loss of consciousness. The mutation results in faster inactivation time constants for the sodium channel and an inability of the inactivation gates to remain closed, leading to a "bursting mode" current. Computer models of the mutation replicate these effects on channel kinetics and the prolonged action potential.

1. LQT Syndrome 3
GROUP 4
Matthew Argentieri
Michelle Hung
Susan Mathew
Sweta Roy
Yarden Segal
Dikesh Shrestha

2. Background
• LQT3 is an autosomal dominant disease.
– This mutation affects the inactivation gate of the
sodium channel and causes a gain of function of
sodium current.
– Primary LQT3 mutation is ΔKPQ
• ΔKPQ is the deletion of lysine, proline, and glutamine
between domains III and IV.

3. Background

4. Symptoms
• Arrhythmia
• Partial or total loss of
consciousness
• Abdominal pain and
GI complications
• Clinical features
– Long ST
segments with a
late appearing T
wave
– Has QT >490+/-
40 ms

5. Factors
• There was no voltage shift, no change
in channel conductance, and no change
in ionic concentrations.
• Changes in gate kinetics (time
constants) and a new sustained inward
current were the only factors discerning
LQT3 from wild-type cells.

6. Time Constants
• Activation gate unaffected
• The time constants for the inactivation
gates (fast and slow) changed.
– Wild Type
• τ fast : 1.47 +/- 0.11 ms
• τ slow: 8.59 +/- 0.71 ms
– Mutant
• τ fast : 0.98 +/- 0.07 ms
• τ slow: 5.40 +/- 0.55 ms

7. Approach
• Multiplied time constants by a scaling
factor
– τfast : 66.67% (2/3)
– τslow : 62.86% (540/859)
• Altered steady-state inactivation curves
(minimum probability of inactivation)
– Fast : 1%
– Slow: 3%

8. Modified Steady State Curves
BLUE CURVE: Modified fast inactivation steady
state curve – levels out at 1% probability of
being open (i.e. never reaches 0%)
RED CURVE: Modified
slow inactivation steady
state curve – levels out
at 3% probability of
being open (i.e. never
reaches 0%)

9. MATLAB CODE
h_ss(index) = alpha_h/(alpha_h+beta_h);
if h_ss(index) <=0.01
h_ss(index) = 0.01;
end
j_ss(index) = alpha_j/(alpha_j+beta_j);
if j_ss(index) <=0.03
j_ss(index) = 0.03;
end
tau_h = 1.0/(alpha_h+beta_h)*(2/3);
tau_j = 1.0/(alpha_j+beta_j)*(540/859);

10. Preview of the GUI

11. Preview of the GUI
ΔKPQ Mutant Cardiomyocyte Action Potential
Normal Cardiomyocyte Action Potential

12. Conclusions
• Action potential duration is elongated
due to longer repolarization
– Increased time of repolarization due to
sustained inward sodium current
– Diastolic Interval is reduced
• Time constants for LQT3 are smaller and
cause faster inactivation
• Inactivation gates fail to remain
inactivated
– Leads to bursting mode current

13. THANK YOU!
Visit our educational website at:
http://mysbfiles.stonybrook.edu/~margentieri

14. References
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