What is the role of the LQT3 gene in the etiology of long QT syndrome (LQTS)?

Updated: Nov 29, 2017
  • Author: Ali A Sovari, MD, FACP, FACC; Chief Editor: Mikhael F El-Chami, MD  more...
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Answer

In LQT3, caused by mutations of the SCN5A gene for the sodium channel, a gain-of-function mutation causes persistent inward sodium current in the plateau phase, which contributes to prolonged repolarization. [10] Some loss-of-function mutations in the same gene may lead to different presentations, including Brugada syndrome. More than 50 mutations have been identified in this gene.

Cardiac events are less frequent in congenital LQT3 than in LQT1 and LQT2, but they are more likely to be lethal (20% mortality with cardiac events in families with LQT3 mutations; 4% in those with an LQT1 or LQT2 mutation). [10]

In some patients, caveolae proteins have been recognized as responsible for the increased sodium current in LQTS3. [11] Caveolae are small (50-100 nm) microdomains that exist on the membrane of a variety of cells, including cardiac myocytes and fibroblasts. Some ion channels, and in particular the SCN5A-encoded voltage-gated sodium channels, are mainly co-localized with caveolae on the membrane. Thus, absence or abnormal formation of caveolae may have some effects on the availability of sodium channels. For example, Vatta and colleagues demonstrated that mutations in caveolin-3 protein exist in LQTS3 and that they can cause an increase in late sodium current. [11]

Nevertheless, caveolae are present in the membrane of many other cell types and are also involved in many cellular activities, thus, their impairment is expected to be associated with multisystemic diseases. For example, Rajab and colleagues reported genetic mutations resulting in defective caveolae in families with congenital generalized lipodystrophy who have several systemic manifestations, such as hypertrophic pyloric stenosis, impaired bone formations, ventricular arrhythmia, and sudden cardiac death. [12] The fact that mutations in proteins associated with ion channels may result in a change in the availability of channels on the membrane, and therefore a significant change in total current, has added another window for investigating the genetic abnormalities resulting in LQTS.


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