DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.

ABSTRACT:

Rationale

Mutations in the LMNA gene, encoding LMNA (lamin A/C), are responsible for laminopathies. Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in laminopathies.

Objective

To gain insights into the molecular pathogenesis of DCM in laminopathies.

Methods and results

We generated a tet-off bigenic mice expressing either a WT (wild type) or a mutant LMNA (D300N) protein in cardiac myocytes. LMNA^D300N mutation is associated with DCM in progeroid syndromes. Expression of LMNA^D300N led to severe myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. Administration of doxycycline suppressed LMNA^D300N expression and prevented the phenotype. Whole-heart RNA sequencing in 2-week-old WT and LMNA

SUBMITTER: Chen SN 

PROVIDER: S-EPMC6460911 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature