IDENTIFICATION OF NOVEL VARIANTS IN BRUGADA SYNDROME CANDIDATE GENES

Uschi Peeters, Mary-Louise Bonduelle, Liszl Peirsman, Kristof Endels, Evrim Comurcu-Bayrak, Pedro Brugada, Karine Breckpot, Sonia Van Dooren

Research output: Chapter in Book/Report/Conference proceedingMeeting abstract (Book)Research

Abstract

Background: Brugada syndrome (BrS) is one of the causes of sudden cardiac death in young people. In 20% of BrS patients mutations are found in the SCN5A gene, coding for the beta-subunit of the cardiac sodium channel. Other genes have also been associated with BrS, among which two of the four beta-subunits genes that code for auxiliary subunits of SCN5A: SCN1B and SCN3B. These beta-subunits regulate expression and gating properties of the beta-subunit.
Aim of the study & methods: After exclusion of mutations in the SCN5A gene, BrS patients were screened using Sanger sequencing for variations in the four beta-subunits (SCN1B, SCN2B, SCN3B and SCN4B) in order to identify novel causal mutations.
Results: Two variants were found that possibly influence ion channel protein function. The first variant in the SCN1Bb isoform induces a frame shift resulting in an extended C-terminal region due to abolishment of the stop codon. An extended SCN1Bb protein might show an altered interaction with the SCN5A protein (Watanabe et al, jci, 2008).
A second variant was identified in SCN4B; a protein that has not been associated with BrS yet. This variant is a nucleotide change upstream of the start codon in the minimal promoter region. In silico comparison of this promoter region in different species demonstrates that this variant occurs in a highly conserved region, this variant might cause an altered expression of SCN4B.
We hypothesize that both variants can affect the sodium current in the cell by changing beta-subunit sodium channel (SCN5A) characteristics and thus cause BrS.
Future perspectives: We want to test our hypotheses performing functional studies. Promoter function in the SCN4B gene will be analyzed using a promoter GLuc reporter construct comparing the wild type and the variant promoter in 293T cells. The effect on SCN1Bb can be tested by co-expressing the variant with the SCN5A channel in H9c2(2-1) cells, and determining the (co-)localization, the expression profile and the electrophysiological properties of the sodium channel.
Original languageEnglish
Title of host publicationSecond PhD day of the Medical Campus VUB, Brussels Belgium
Publication statusPublished - 2012

Keywords

  • Brugada Syndrome
  • beta-subunits
  • SCN1-4B
  • variants

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