Current insights intoLMNAcardiomyopathies: Existing models and missing LINCs

Abstract

The nuclear lamina is a critical structural domain for the maintenance of genomic stability and whole-cell mechanics. Mutations in the LMNA gene, which encodes nuclear A-type lamins lead to the disruption of these key cellular functions, resulting in a number of devastating diseases known as laminopathies. Cardiomyopathy is a common laminopathy and is highly penetrant with poor prognosis. To date, cell mechanical instability and dysregulation of gene expression have been proposed as the main mechanisms driving cardiac dysfunction, and indeed discoveries in these areas have provided some promising leads in terms of therapeutics. However, important questions remain unanswered regarding the role of lamin A dysfunction in the heart, including a potential role for the toxicity of lamin A precursors in LMNA cardiomyopathy, which has yet to be rigorously investigated.

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

“…Expression of the mutant LamC resulted in defective ostia, noncontractile region(s) of the heart, and loss of heartbeat, an indicator of conduction defects (Figure 1c), which are observed in human LMNA patients (Arbustini et al., 2002; Brayson & Shanahan, 2017; Malhotra & Mason, 2009; Wolf et al., 2008). In addition to severe cardiac defects, heart‐specific expression of R205W and G489V had a drastic impact on the lifespan for both female and male adults compared to controls (Figure 1d, e).…”

“…Mutations in the human LMNA gene are associated with a collection of diseases called laminopathies in which the most common manifestation is progressive cardiac disease (Brayson & Shanahan, 2017; Heller et al., 2017; Marian, 2017; Naetar, Ferraioli & Foisner, 2017). We have generated Drosophila melanogaster models of age‐dependent cardiac dysfunction.…”

Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

“…Besides, questions regarding the role of Ca 2+ signaling and myocardial energetics remain unanswered [28]. Here we present the cellular study of the Lamin A D243Gfs*4 truncating mutant associated to a severe cardiomyopathy outcome.…”

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

“…Laminopathies involve a wide spectrum of diseases affecting striated muscle, the heart, the adipose tissue, and peripheral nerves or can be a multi-organ and multi-system disease as in the Hutchinson-Gilford progeria syndrome [3,5] and cardiac disturbances may be present in patients with quite different phenotypes due to lamin A/C mutations.…”