Transcript Presentation2.ppt

Long QT Syndrome Type 3 (LQT 3)
Mutations in SCN5A (Na+ Channel, INa)
BME 301
Qaiyim Cheeseborough,
Victoria Reyes, Kin Siu
Introduction to LQT
Disorder caused by
mutations in cardiac
ion channels
Most associated with
K+ channels
LQT III
Abnormalities in the Na+ channel
Incomplete inactivation
Symptoms
Fainting (syncope)
Seizures
Cardiac arrest
Sudden Death
Diagnosis
Diagnosis is
preformed by
analyzing the ECG
readings in response
to the T – wave.
A autopsy may be
conducted of LQT 3
syndrome through
examining the SCN5A
gene
Normal ECG
Long QT syndrome
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
Fatal arrhythmias – 39% at rest, 32% during
exercise and emotional stress
Protein characteristics
2016 amino acids
Sequence – 4 internal
repeats, with 5 hydrophobic
segments and 1 positively
charged segment each
Protein Function
Forms voltagedependent, sodium
selective channel
Positively charged
segments most likely
the voltage sensors
Responsible for initial
upstroke in an action
potential
Protein Mechanism for Disorder
LQT III caused by incomplete inactivation
III-IV linker region as blocking particle
C-Terminus as a docking station
Mutations at these regions can cause failure
in inactivation
Strategy for Java simulation
Change inactivation gate so that some are
open at all times.
Values of h and j can not be above 1
Specific changes I
Same changes to h and j
h_ss is the steady state value of h
Change : h_ss = x + ((1.0 – x) * h_ss)
X is the minimum value of h
Results
Green shows normal action potential, yellow
is modified version of LQT-3.
Percent of action potential
increase
Sensitivity analysis
45
40
35
30
25
20
15
10
5
0
1
1.5
2
2.5
Min percent value of sodium inactivation gates h and j
3
Conclusions
Changes made resulted in action potentials
similar to disorder.
Mode of changes resemble mechanism of
disease.
Web site
http://www.ic.sunysb.edu/Stu/vreyes/Index.htm
References
Neuromuscular Disease Center. ION CHANNELS, TRANSMITTERS, RECEPTORS
& DISEASE. 10 Feb 2000.
http://medlib.med.utah.edu/kw/ecg/ecg_outline/Lesson4/#QTinterval
http://www.neuro.wustl.edu/neuromuscular/mother/chan.html
Bennett, P.B., Yazawa K, Makita N, George AL Jr. (1995) Molecular mechanism for an
inherited cardiac arrhythmia. Nature 1995 Aug 24;376(6542):683-5
Clancy, C.E., Tateyama, M., Kass, R.S.. (2002) Insights into the molecular
mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. . Clin.
Invest. 110:1251-1262
ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE.
http://www.neuro.wustl.edu/neuromuscular/mother/chan.html#lqt
J. Biol. Chem., Vol. 277, Issue 11, 9233-9241, March 15, 2002
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