Fig. 7: Proposed work model.

The novel mutation A388fs in the LMNA gene leads to lamin A/C haploinsufficiency. This causes abnormal Ca²⁺ handling, arrhythmias, and a disformed nuclear envelope (NE) in mutant iPSC-CMs. The reduced expression of lamin A/C in A388fs iPSC-CMs leads to accelerated degradation of the lamin A-binding protein sirtuin 1 (SIRT1), resulting in mitochondrial dysfunction and oxidative stress. On one hand, elevated ROS activates Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). This then promotes ryanodine receptor 2 (RYR2)-mediated sarcoplasmic reticulum (SR) Ca²⁺ leak and subsequently causes elevated diastolic [Ca²⁺]_i, abnormal Ca²⁺ handling, and arrhythmias in A388fs iPSC-CMs. Rescue of these phenotypes can be achieved via the application of the CaMKII inhibitor KN93. On the other hand, excessive ROS production accelerates the accumulation of the nuclear protein SUN1, which then contributes to NE deformation in A388fs iPSC-CMs. In this case, both arrhythmias and nuclear defects can be rescued via the application of SIRT1 activators (either SRT1720 or resveratrol) or ROS scavengers (either NAC or mitoTEMPO). Figure 7 created with BioRender.com was released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.