Current insights intoLMNAcardiomyopathies: Existing models and missing LINCs

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.