To gain insights into the molecular pathogenesis of DCM caused by LMNA mutation, a doxycycline-inducible (Dox-Off) gene expression system was used to express either a wild type (WT) or a mutant LMNA containing the pathogenic variant p.Asp300Asn (LMNAD300N) in cardiac myocytes. The LMNAD300N is associated with DCM in patients with atypical progeroid/Werner syndrome and non-syndromic cardiac progeria. Expression of the mutant LMNAD300N protein in cardiac myocytes led to severe fibrosis, apoptosis, cardiac dysfunction, and premature death.  RNA-seq was performed (prior to onset of cardiac dysfunction) to identify  gene signatures and transcriptional regulators responsible for this phenotype. Mechanistic studies identified activation of E2F/TP53/DDR, as a major mechanism responsible for the pathogenesis of DCM caused by the LMNAD300N mutation. SOURCE: Ali,J,Marian (Ali.J.Marian@uth.tmc.edu) - Marian Lab UTHSC, Houston

Pluto Bioinformatics

GSE123916: TP53/DNA Damage Response Pathway is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Caused by Lamin A/C Mutations