Key result
TRPM4 mutation p.I377T increases Ca2+ sensitivity ~2.6-fold and drives VT susceptibility in aged mice.
Why the study?
Multiple mutations in TRPM4 have been associated with progressive cardiac conduction disease, but whether such mutations directly cause electrophysiological alterations in cardiac muscle cells was unclear.
Population
HEK-293T cells, ventricular cardiomyocytes, and young and aged wildtype and mutant (Trpm4I377T/I377T) mice
Comparison
TRPM4 mutant (p.I376T / murine p.I377T) vs wildtype
Design
In vitro, ex vivo, and in vivo preclinical electrophysiological study
Authors
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Does not yet support TRPM4-targeted therapy in PCCD; extends mechanistic insight in animal models but leaves human causality open.
Effect estimate: 2.61x increase
The TRPM4 mutation p.I377T causes a progressive cardiac conduction disease-like phenotype and increases arrhythmia susceptibility in mice, strongly indicating the human p.I376T mutation is disease-causing.
Pironet et al. (2026) studied Progressive cardiac conduction disease (PCCD). TRPM4 mutation p.I377T vs. Wildtype was evaluated on Electrophysiological alterations and arrhythmia sensitivity (2.61x increase). The TRPM4 mutation p.I377T caused a 2.61-fold increase in Ca2+ sensitivity and increased susceptibility to self-sustaining ventricular tachycardia in aged mutant mice compared to wildtype.
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