JCI online early table of contents: May 8, 2008

The SCN1B gene carries the information required for making two related sodium channel beta-subunits known as beta-1 and beta-1B. In the study, expression of the intermediates that translate the genetic information into the beta-1 and beta-1B proteins was found to be high in normal human heart tissue, in particular in the cells that conduct the electrical impulses that coordinate the beating of the heart. This was consistent with the hypothesis that mutant forms of these proteins might cause cardiac arrhythmias and/or defective conduction of the electrical impulses that regulate the heartbeat (the defects that lead to Brugada syndrome and cardiac conductance disease). Functional evidence to support this hypothesis was provided by the observation that the mutant forms of beta-1 and beta-1B reduced Nav1.5 sodium currents in cell lines and led the authors to suggest that mutations in SCN1B can make individuals susceptible to Brugada syndrome and/or cardiac conductance disease.

TITLE: Sodium channel beta-1 subunit mutations associated with Brugada syndrome and cardiac conductance disease in humans

AUTHOR CONTACT:
Connie R. Bezzina
University of Amsterdam, Amsterdam, The Netherlands.
Phone: 31-20-5665403; Fax: 31-20-6976177; E-mail: .

View the PDF of this article at: https://www.the-jci.org/article.php?id=33891

CARDIOLOGY: Of mice, rabbits, and men: new rabbit model of sudden cardiac death provides insight into the human disease

Individuals with long QT syndrome (LQTS) are at increased risk of sudden death due to irregular heartbeats (also known as a cardiac arrhythmias). Although mutations in several genes have been shown to cause the disease, the most commonly affected genes are KCNQ1 and KCNH2. New insight into the mechanisms by which these mutations might produce an irregular heartbeat in humans has been provided by Gideon Koren and colleagues, at Brown University, Providence, who have generated two rabbit models of LQTS.

Although mouse models of LQTS have enhanced our understanding of many aspects of the disease, there are important differences between mice and humans that limit the applicability of some studies to individuals with LQTS. Many of these differences are not found in rabbits, the authors therefore generated rabbits expressing either KCNQ1 or KCNH2 mutants that generate proteins with the same functional defect as found in individuals with LQTS. The heart defects observed in the rabbits mirrored those observed in individuals with LQTS and more than 50% of the rabbits carrying the KCNH2 mutant died suddenly due to irregular heartbeats in their first year of life. The proteins generated by the KCNQ1 and KCNH2 mutants prevented proteins generated by the corresponding nonmutant form of the gene from working and, importantly, no compensation for the loss of function of either protein was observed. As compensation for the loss of function of the proteins generated by the KCNQ1 and KCNH2 mutants is observed in mouse models of LQTS these data provide important insight into the mechanisms underlying the disease.