Long QT syndrome (LQTS) is a rare heart condition that occurs in 1 of every 2000-2500 people worldwide. It’s caused by mutations in a variety of ion channels that cause a prolongation in QT interval. The most prevalent forms are LQTS1 (44%-50%), LQTS2 (40%-45%), LQTS3 (5%-15%).
This site will focus on LQTS-1: the most prevalent subtype of LQTS. It’s caused by a mutation in the IKs channel, which is formed by the coassembly of pore-forming α (KCNQ1) subunit and modulatory β (KCNE1) subunit. The following image displays the protein assembly of the alpha and beta units into the Ks Channel.
There are two proteins involved: KvLQT1 and MinK Protein. Function of the KvLQT1 is to repolarize the cardiac tissue after action potential. It transports water and salt in epithelial tissues, and it produces a slow activating and deactivating potassium current which creates a voltage-gated potassium channel. MinK is expressed in ventricular myocytes and sinoatrial node cells. It’s necessary for the stimulation of the slow delayed potassium rectifier current (IKs), and it interacts with the KvLQT1 channel causing conformational changes resulting in greater current amplitudes.
The general LQTS can be caused by genetic mutations or medicinal alterations. In regards to genetics a mutated gene in a pacemaker cell can make too few, dysfunctional ion channels, or both. And if the mutation occurs such that is throughout the genetic code it can be passed down to future generations. A loss-of-function mutations in KCNQ1 cause long QT syndrome type 1 (LQT1). This is caused by disruption in protein folding, assembly and trafficking. Gain-of-function mutations have been implicated in short and long QT syndrome. Mutations in the S3 domain of KCNQ1 subunit have the most severe effect on the IKs kinetics. Some mutations in the S3 transmembrane domain include V205M, I204M, and S209F.
A variety of medicines can cause the syndrome, usually by inhibiting hERG1 which disrupts IKr. These include, but are not limited to: Antihistamines & decongestants, diuretics, antibiotics, antiarrhythmic medicines, antidepressant and antipsychotic medicines, and cholesterol-lowering medicines and some diabetes medicines.
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