Molecular Genetics and Functional Anomalies in a Series of 248 Brugada Cases with 11 Mutations in the TRPM4 Channel

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.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…A subset of patients with Brugada syndrome who had a bifascicular block and/or a complete right bundle branch block was recently reported. In these patients, four TRPM4 mutants were described, resulting in either decreased expression (P779R and K914X) or increased expression (T873I and L1075P) of TRPM4 channels (Liu et al, 2013c).…”

Increased β-Adrenergic Inotropy in Ventricular Myocardium From Trpm4 −/− Mice

“…13 Interest in the physiological role of TRPM4 in the heart has further risen with the description of mutations in the TRPM4 gene that are linked to autosomal dominant forms of cardiac conduction diseases, including progressive familial heart block type I and Brugada syndrome. [14][15][16] Heterologous overexpression of mutant channels in human embryonic kidney cells indicates that these mutations can lead to increased or decreased expression and activity of TRPM4 proteins, [14][15][16][17] which might contribute through an as yet unknown mechanism to the above-mentioned syndromes. Overall, the contribution of TRPM4 proteins to the dynamics of cytosolic Ca 2+ handling in ventricular cardiomyocytes and to contractility of the heart and its relevance during, for example, neurohumoral stress has not been elucidated to date.…”

Genetics of Sudden Cardiac Death

“…A single study reported that ≈6% of BrS cases carry mutations in the transient receptor potential melastatin protein number 4 or TRPM4 gene encoding for a calcium-activated nonselective cation channel, member of a large family of transient receptor potential genes. 90 These finding, however, still need confirmation. Recently, another study reported that mutations in SCN10A account for 16% of patients with typical BrS identified in a cohort of 150 BrS affected individuals.…”