Abstract
Brugada syndrome (BrS) is a condition defined by ST-segment alteration in right precordial leads and a risk of sudden death. Because BrS is often associated with right bundle branch block and the TRPM4 gene is involved in conduction blocks, we screened TRPM4 for anomalies in BrS cases. The DNA of 248 BrS cases with no SCN5A mutations were screened for TRPM4 mutations. Among this cohort, 20 patients had 11 TRPM4 mutations. Two mutations were previously associated with cardiac conduction blocks and 9 were new mutations (5 absent from ∼14′000 control alleles and 4 statistically more prevalent in this BrS cohort than in control alleles). In addition to Brugada, three patients had a bifascicular block and 2 had a complete right bundle branch block. Functional and biochemical studies of 4 selected mutants revealed that these mutations resulted in either a decreased expression (p.Pro779Arg and p.Lys914X) or an increased expression (p.Thr873Ile and p.Leu1075Pro) of TRPM4 channel. TRPM4 mutations account for about 6% of BrS. Consequences of these mutations are diverse on channel electrophysiological and cellular expression. Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to BrS.
Highlights
Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads (V1– V3) of the electrocardiogram (ECG) with an associate risk of cardiac arrhythmia [1]
We addressed the question whether BrS cases could be attributed to transient receptor potential melastatin protein number 4 (TRPM4) mutations since BrS is frequently associated with cardiac conduction anomalies
All participants were screened for mutation in the gene encoding the alpha subunit of the sodium channel gene (SCN5A) and 83 patients (25%) had a SCN5A variant
Summary
Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads (V1– V3) of the electrocardiogram (ECG) with an associate risk of cardiac arrhythmia [1]. The ECG signature of BrS is transient and can be unmasked by administration of sodium channel blockers such as ajmaline or flecainide [2,4]. There are internationally accepted criteria to establish a diagnosis of BrS [5]. Numerous environmental factors influence BrS clinical and ECG expressivity, it is commonly accepted that it is a genetic disease with usually an autosomal dominant pattern of inheritance [6,7]. Since 1998, it has been established that about 15–25% of BrS cases can be linked to mutations in SCN5A that encodes the alpha subunit of cardiac sodium channel Nav1.5 [8]. Several other genes have been implied in BrS such as GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, SCN3B, KCNJ8 [9], CACNA2D1 [10], KCND3 [11] and MOG1 [12] (for a review see [13])
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