The Broad Spectrum of LMNA Cardiac Diseases: From Molecular Mechanisms to Clinical Phenotype

Abstract

Mutations of Lamin A/C gene (LMNA) cause laminopathies, a group of disorders associated with a wide spectrum of clinically distinct phenotypes, affecting different tissues and organs. Heart involvement is frequent and leads to cardiolaminopathy LMNA-dependent cardiomyopathy (LMNA-CMP), a form of dilated cardiomyopathy (DCM) typically associated with conduction disorders and arrhythmias, that can manifest either as an isolated event or as part of a multisystem phenotype. Despite the recent clinical and molecular developments in the field, there is still lack of knowledge linking specific LMNA gene mutations to the distinct clinical manifestations. Indeed, the severity and progression of the disease have marked interindividual variability, even amongst members of the same family. Studies conducted so far have described Lamin A/C proteins involved in diverse biological processes, that span from a structural role in the nucleus to the regulation of response to mechanical stress and gene expression, proposing various mechanistic hypotheses. However, none of those is per se able to fully justify functional and clinical phenotypes of LMNA-CMP; therefore, the role of Lamin A/C in cardiac pathophysiology still represents an open question. In this review we provide an update on the state-of-the-art studies on cardiolaminopathy, in the attempt to draw a line connecting molecular mechanisms to clinical manifestations. While investigators in this field still wonder about a clear genotype/phenotype correlation in LMNA-CMP, our intent here is to recapitulate common mechanistic hypotheses that link different mutations to similar clinical presentations.

A splicing LMNA mutation causing laminopathies accompanied by aortic valve malformation

“…In addition, aortic valve morphogenesis arises at embryonic day (E)9.5, and the mature valves with fine defined leaflets are shaped at about E16.5 in mouse embryos, 16 while Lamin A/C start to be expressed in mouse extra-embryonic tissues around E8-9 and in the embryo around E10-12, playing an important role in cell differentiation, lineage specification, and tissue development. 2 Furthermore, the proper remodeling of aortic valves depends on multiple molecular pathways, especially Notch signaling. Recently, Lamin A has been reported to closely interact with Notch signaling and affect cell differentiation, even in cells of close developmental origin, such as cardiac mesenchymal cells and valve interstitial cells.…”

“…Pasotti et al reported that the cumulative event‐free survival was only 60% at 5‐years after LMNA ‐CMP diagnosis, and 45% of the events were sudden cardiac death or aborted sudden cardiac death 8 . However, only half of the patients with LMNA mutations had left ventricular dysfunction at the first visit, 9 owing to the age‐dependent penetrance of LMNA ‐CMP with development after the second decade of life in the majority of carriers and complete penetrance at 60 years of age 2 …”

“…1 With the development of genetic analysis for inherited and multisystem diseases, a total of 498 LMNA mutations have been found and associated with more than 15 different phenotypes. 2 Cardiac phenotypes are the most severe and are often lethal before the onset of significant and severe neuromuscular symptoms. In this report, we present the case of a patient who experienced slow progressive muscle weakness and cardiac abnormalities caused by a novel LMNA mutation.…”

“…The gene variant was first identified in a patient who had EDMD with cardiac manifestations, conduction system disorder, and dilated cardiomyopathy (DCM) 1 . With the development of genetic analysis for inherited and multisystem diseases, a total of 498 LMNA mutations have been found and associated with more than 15 different phenotypes 2 . Cardiac phenotypes are the most severe and are often lethal before the onset of significant and severe neuromuscular symptoms.…”

Genetic Cardiomyopathies: The Lesson Learned from hiPSCs

“…Lamin A/C are classified as intermediate filament proteins, the main constituent of the nuclear envelope with a structural role in the nucleus and the ability to regulate gene transcription through either direct or indirect modulation of chromatin organization, DNA replication, and signal transduction pathways [ 49 ]. In comparison to TTN variants, LMNA mutations most commonly result in brady- and tachy-arrhythmias together with cardiomyopathy, with a resulting high risk of sudden cardiac death often requiring pacemaker and/or defibrillator implantations [ 45 , 50 ].…”