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.
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.
Effect estimate: 2.61x increase
Abstract Background Previous studies have suggested that progressive cardiac conduction disease (PCCD) can result from mutations in ion channels such as TRPM4. Multiple mutations in TRPM4 have already been associated with PCCD, but it is unclear whether such mutations are a direct cause of electrophysiological alterations in cardiac muscle cells. Here, we focus on delineating the in vitro and in vivo electrophysiological parameters of the disease-associated mutation p.I376T and its murine orthologue p.I377T. Materials & Methods: We performed in vitro electrophysiology and calcium imaging on transiently-transfected HEK-293T cells and ventricular cardiomyocytes as well as ex vivo cardiac optical mapping and in vivo intracardiac electrocardiogram measurements in young (20-40 weeks) and aged (50+ weeks) wildtype and mutant (Trpm4I377T/I377T) mice. Results Using whole-cell patch clamp in HEK-293T cells, we observed that the disease-associated p.I376T mutation causes gain-of-function in TRPM4 activity. Inside-out recordings showed a 2.61x increase in Ca2+ sensitivity. Similar results were obtained in the murine orthologue of this disease-associated mutation. A mouse line carrying this mutation was generated. Optical mapping of ex vivo hearts from aged mutant mice revealed significant slowing of the conduction velocity in both the left and right ventricle, compared to aged WT littermates. Interestingly, aged mutant mice also exhibited a lower effective refractory period of the ventricle. High frequency, intracardiac burst pacing showed that aged mutant mice were more prone to self-sustaining ventricular tachycardia. Conclusion Our data demonstrate that the TRPM4 mutation p.I377T causes a PCCD-like phenotype and a progressive increase in arrhythmia susceptibility in mice and, importantly, strongly indicate that the PCCD-associated mutation p.I376T is disease-causing. While additional, unidentified genes may also contribute to the disease-trigger mechanism of a more severe PCCD-associated phenotype, it is clear that TRPM4 mutations play a crucial role in PCCD.
Pironet et al. (Fri,) conducted a other in 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.