Unveiling the effects of a Tbx20 truncating variant in dilated cardiomyopathy: insights from a new mouse model

Abstract Introduction Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by dilatation of one or both ventricles with impaired contractility. The pathophysiological mechanisms of DCM range from monogenic causes to the interplay of genetic abnormalities and environmental triggers. Initially, genetic causes were thought to be associated with mutations in genes encoding proteins that are localized only in the cytoskeleton and sarcomere; but cardiac transcription factors have also been described to be involved in both familial and sporadic cases of DCM1. Recent studies implicate loss-of-function variants of T-Box Transcription Factor 20 (Tbx20) in DCM. In this context, we focused on the p.His225Glnfs*22 mutation, recently reported in humans. This Tbx20 truncating variant (Tbx20tv) was identified in 15 patients from two families, whose affected members had DCM2. Purpose We aimed to develop a new mouse model with this Tbx20tv and conduct a longitudinal study to determine the onset and progression of DCM caused by this mutation. Methods The CRISPR-Cas9 system components were microinjected into mouse zygotes, which were then transferred into pseudopregnant female mice, leading to the F0 chimera generation. We identified risk patterns associated with DCM by analysing survival curves and assessing longitudinal changes in ECG and echocardiography at three time points: 12 weeks, 24 weeks, and 54 weeks, in the mutants’ mice F3 generation (Tbx20.delT672) and wild type controls. Results Tbx20.delT672 mice had longer QRS duration (ms) at 24 weeks. In addition, the incidence of ECG abnormalities, such as ST-segment depression and notched QRS, also increased from week 12 onwards, along with the appearance of arrhythmias at 54 weeks. Furthermore, Tbx20 mutant mice showed an increase in diastolic volume and E/A ratio (mm/s) from week 24, with a decrease in EF (%) at week 54, which was significantly lower in males. The treadmill fatigue test showed a shorter moved distance (cm) by Tbx20.delT675 mice, with a lower percentage of movement in the final stages of the implemented protocol. Finally, no differences were observed in the survival curve. Conclusions Our model reproduces the dilated phenotype observed in patients with the Tbx20tv, suggesting intraventricular conduction delay or block as a potential contributor to DCM.