TRPM4 – Brugada syndrome

Brugada syndrome (BrS) is an inherited arrhythmia predisposing to sudden cardiac death, with about 20% of cases unexplained by SCN5A. Heterozygous variants in TRPM4 have been identified in 20 of 248 unrelated BrS probands (∼6%) screened without SCN5A mutations, encompassing 11 distinct variants including missense and truncating changes (PMID:23382873). A single BrS patient with compound SCN5A and TRPM4 variants further underscores mutation load effects (PMID:28494446), while a compound‐heterozygous TRPM4 null case suggests heterozygous loss‐of‐function may not suffice for disease in isolation (PMID:30142439). No robust familial segregation has been demonstrated.

Functional studies reveal that BrS‐associated TRPM4 mutants (e.g., c.2740A>T (p.Lys914Ter)) cause either reduced or increased channel expression and current density in vitro, consistent with disrupted membrane excitability (PMID:23382873). In vivo, Trpm4−/− mice display decreased peak Na⁺ currents and slowed ventricular conduction, mirroring BrS electrophysiology (PMID:33810249). The mechanism involves altered TRPM4‐mediated depolarizing currents that secondarily affect Nav1.5 availability. Conflicting autosomal recessive findings highlight the need for further family‐based studies. Key take-home: TRPM4 variants account for a minority of BrS cases and can inform genetic diagnosis and risk stratification.

References

• PLoS One • 2013 • Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel. PMID:23382873
• International Journal of Molecular Sciences • 2021 • Deletion of Trpm4 Alters the Function of the Nav1.5 Channel in Murine Cardiac Myocytes. PMID:33810249
• Cardiology • 2017 • Mutation Load of Multiple Ion Channel Gene Mutations in Brugada Syndrome. PMID:28494446
• European Journal of Medical Genetics • 2019 • TRPM4 mutations to cause autosomal recessive and not autosomal dominant Brugada type 1 syndrome. PMID:30142439

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