LQT Syndrome 3

GROUP 4Matthew Argentieri

Michelle HungSusan Mathew

Sweta RoyYarden Segal

Dikesh Shrestha

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.

Background

• Arrhythmia

• Partial or total loss of consciousness

• Abdominal pain and GI complications

Symptoms

• Clinical features– Long ST

segments with a late appearing T wave

– Has QT >490+/-40 ms

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.

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

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%

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%)

MATLAB CODE

h_ss(index) = alpha_h/(alpha_h+beta_h);if h_ss(index) <=0.01h_ss(index) = 0.01; end

j_ss(index) = alpha_j/(alpha_j+beta_j); if j_ss(index) <=0.03j_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);

Preview of the GUI

Preview of the GUI

Normal Cardiomyocyte Action Potential

ΔKPQ Mutant Cardiomyocyte Action Potential

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

THANK YOU!

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References

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