Perinuclear organelle trauma at the nexus of cardiomyopathy pathogenesis arising from loss of function LMNA mutation.

Abstract

Over the past 25 years, nuclear envelope (NE) perturbations have been reported in various experimental models with mutations in the LMNA gene. Although the hypothesis that NE perturbations from LMNA mutations are a fundamental feature of striated muscle damage has garnered wide acceptance, the molecular sequalae provoked by the NE damage and how they underlie disease pathogenesis such as cardiomyopathy (LMNA cardiomyopathy) remain poorly understood. We recently shed light on one such consequence, by employing a cardiomyocyte-specific Lmna deletion in vivo in the adult heart. We observed extensive NE perturbations prior to cardiac function deterioration with collateral damage in the perinuclear space. The Golgi is particularly affected, leading to cytoprotective stress responses that are likely disrupted by the progressive deterioration of the Golgi itself. In this review, we discuss the etiology of LMNA cardiomyopathy with perinuclear 'organelle trauma' as the nexus between NE damage and disease pathogenesis.