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Genetics, molecular mechanisms and management of long QT syndrome
1Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston 77030, USA. qwang@bcm.tmc.edu
Insights
Long QT syndrome (LQT) causes sudden cardiac death. Treatments targeting specific gene mutations, like sodium channel blockers for SCN5A and potassium for HERG, show promise for LQT patients.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Cardiac arrhythmias, including Long QT syndrome (LQT), are a significant cause of sudden cardiac death.
- LQT is linked to specific genetic mutations affecting cardiac ion channels.
Purpose of the Study:
- To review the genetic basis of LQT and the mechanisms of associated cardiac arrhythmias.
- To discuss current and potential therapeutic strategies for LQT based on genetic findings.
Main Methods:
- Review of identified LQT genes (KVLQT1, HERG, SCN5A, MinK) and their encoded ion channels.
- Analysis of mutation mechanisms (dominant-negative, loss-of-function) and their impact on cardiac currents.
- Evaluation of treatment efficacy for specific LQT types.
Main Results:
- Mutations in SCN5A (LQT3) lead to abnormal sodium channel activity, treatable with sodium channel blockers like mexiletine.
- Mutations in HERG (LQT2) and KVLQT1/MinK (LQT1/LQT5) affect potassium channels, with potential management strategies involving serum potassium levels or channel-specific therapies.
- Genetic testing is available for some LQT patients.
Conclusions:
- Understanding the specific gene mutation in LQT is crucial for developing targeted treatments.
- Therapies aimed at correcting ion channel dysfunction offer potential to reduce sudden cardiac death in LQT patients.
Abstract:
Cardiac arrhythmias cause more than 300,000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome 11p15.5, HERG (LQT2) on chromosome 7q35-36, SCN5A (LQT3) on chromosome 3p21-24, and MinK (LQT5) on chromosome 21q22. SCN5A encodes the cardiac sodium channel, and LQT-causing mutations in SCN5A lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCN5A mutations. HERG encodes the cardiac I(Kr) potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I(Ks) potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I(Ks) potassium channel. Genetic testing is now available for some patients with LQT.