| Autor: |
Adrien eMoreau, Andrew D Krahn, Pascal eGosselin-Badaroudine, George J Klein, Georges eChristé, Yohann eVincent, Mohamed eBoutjdir, Mohamed eChahine |
| Jazyk: |
angličtina |
| Rok vydání: |
2013 |
| Předmět: |
|
| Zdroj: |
Frontiers in Pharmacology, Vol 4 (2013) |
| Druh dokumentu: |
article |
| ISSN: |
1663-9812 |
| DOI: |
10.3389/fphar.2013.00126 |
| Popis: |
Long QT syndrome (LQTS) is a congenital abnormality of cardiac repolarization that manifests as a prolonged QT interval on 12-lead electrocardiograms. The syndrome may lead to syncope and sudden death from ventricular tachyarrhythmias known as torsades de pointes. An increased persistent Na+ current is known to cause a Ca2+ overload in case of ischemia for example. Such increased Na+ persistent current is also usually associated to the LQT3 syndrome. The purpose of this study was to investigate the pathological consequences of a novel mutation in a family affected by LQTS. The impact of biophysical defects on cellular homeostasis are also investigated.Genomic DNA was extracted from blood samples, and a combination of PCR and DNA sequencing of several LQTS-linked genes was used to identify mutations. The mutation was reproduced in vitro and was characterized using the patch clamp technique and in silico quantitative analysis.A novel mutation (Q1476R) was identified on the SCN5A gene encoding the cardiac Na+ channel. Cells expressing the Q1476R mutation exhibited biophysical alterations, including a shift of SS inactivation and a significant increase in the persistent Na+ current. The in silico analysis confirmed the arrhythmogenic character of the Q1476R mutation. It further revealed that the increase in persistent Na+ current causes a frequency-dependent Na+ overload in cardiomyocytes co-expressing WT and mutant Nav1.5 channels, that, in turn, exerts a moderating effect on the lengthening of the action potential duration caused by the mutation.The Q1476R mutation in SCN5A results in a three-fold increase in the window current and a persistent inward Na+ current. These biophysical defects may expose the carrier of the mutation to arrhythmias that occur preferentially in the patient at rest or during tachycardia. However, the Na+ overload counterbalances the gain-of-function of the mutation and is beneficial in that it prevents severe arrhythmias at intermediate he |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
