Current insights into LMNA cardiomyopathies: 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.

Keywords: LINC complex; LMNA; cardiomyocyte; cardiomyopathy; mechanotransduction; nuclear lamina; prelamin A.

Figure 1.

A model unifying the known mechanisms of LMNA cardiomyopathy.

Figure 2.

Etiology of Cardiomyopathy onset and progression. DCM is caused in primary and secondary fashion. In secondary it is due to excessive remodelling of the myocardium because of sustained pressure overload caused by vascular remodelling leading to increased overall blood pressure or aortic valve stenosis (hardening). This usually occurs via an intermediate step in which the heart tissue becomes thicker, known as hypertrophy. Primary DCM is caused predominantly by mutations in proteins of the sarcomere, cytoskeleton, or those involved in Ca²⁺ handling. Additionally, viruses and toxins such as alcohol or chemotherapy agents can initiate DCM independent of vascular remodelling. In this context hypertrophy is bypassed.

Figure 3.

Schematic representation of CM structure. The nuclear lamina associates with LEM proteins i.e., Emerin and heterochromatin on the inner nuclear membrane (INM). Lamins also bind with SUN proteins and nesprins to form the LINC complex, which spans the nuclear envelope (NE), and links to cytoskeletal components (actin, intermediate filaments) via binding domains such as plectin and calponin homology. F-actin extends to the cell periphery and links to membrane anchors such as dystrophin and focal adhesion proteins (e.g. vinculin) thereby creating a mechanical links between the nucleus and ECM. In the context of CMs there may also be interactions with sarcomere structures, which are currently undefined. IFs such as desmin may knit the NE-sarcomere-sarcolemma via the sarco-dystroglycan complex, and provide a mechanical link from the nucleus to the intercalated disc via the cytoskeletal components of the sarcomere and IFs.