Cardiomyopathy Caused by Mutations in Nuclear A-Type Lamin Gene

Heart disease is a major cause of morbidity and premature mortality. Cardiomyopathy is an anatomic and pathologic condition associated with muscle and electrical dysfunction of the heart, often leading to heart failure–related disability. Dilated cardiomyopathy caused by mutations in A-type lamin gene (i.e., LMNA cardiomyopathy) is characterized by an increase in both myocardial mass and volume. The ventricular walls become thin and stretched, compromising cardiac contractility and ultimately resulting in poor left ventricular function. Despite current strategies to aggressively manage “LMNA cardiomyopathy,” the disorder remains a common cause of heart failure with decreased ejection fraction, and a prevalent diagnosis in individuals is referred for cardiac transplantation. Despite progress in reducing “LMNA cardiomyopathy”–related mortality, hospitalizations remain very frequent and rates of readmission continue to rise. It appears important and necessary to further increase our knowledge on the pathophysiology of “LMNA cardiomyopathy” to unveil novel molecular/cellular mechanisms to target future therapeutic approaches

The Pathogenesis and Therapies of Striated Muscle Laminopathies

Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition characterized by early contractures, skeletal muscle weakness, and cardiomyopathy. During the last 20 years, various genetic approaches led to the identification of causal genes of EDMD and related disorders, all encoding nuclear envelope proteins. By their respective localization either at the inner nuclear membrane or the outer nuclear membrane, these proteins interact with each other and establish a connection between the nucleus and the cytoskeleton. Beside this physical link, these proteins are also involved in mechanotransduction, responding to environmental cues, such as increased tension of the cytoskeleton, by the activation or repression of specific sets of genes. This ability of cells to adapt to environmental conditions is altered in EDMD. Increased knowledge on the pathophysiology of EDMD has led to the development of drug or gene therapies that have been tested on mouse models. This review proposed an overview of the functions played by the different proteins involved in EDMD and related disorders and the current therapeutic approaches tested so far

Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations

Publisher Copyright: © 2022, The Author(s).Mutations in the lamin A/C gene (LMNA) cause dilated cardiomyopathy associated with increased activity of ERK1/2 in the heart. We recently showed that ERK1/2 phosphorylates cofilin-1 on threonine 25 (phospho(T25)-cofilin-1) that in turn disassembles the actin cytoskeleton. Here, we show that in muscle cells carrying a cardiomyopathy-causing LMNA mutation, phospho(T25)-cofilin-1 binds to myocardin-related transcription factor A (MRTF-A) in the cytoplasm, thus preventing the stimulation of serum response factor (SRF) in the nucleus. Inhibiting the MRTF-A/SRF axis leads to decreased α-tubulin acetylation by reducing the expression of ATAT1 gene encoding α-tubulin acetyltransferase 1. Hence, tubulin acetylation is decreased in cardiomyocytes derived from male patients with LMNA mutations and in heart and isolated cardiomyocytes from Lmnap.H222P/H222P male mice. In Atat1 knockout mice, deficient for acetylated α-tubulin, we observe left ventricular dilation and mislocalization of Connexin 43 (Cx43) in heart. Increasing α-tubulin acetylation levels in Lmnap.H222P/H222P mice with tubastatin A treatment restores the proper localization of Cx43 and improves cardiac function. In summary, we show for the first time an actin-microtubule cytoskeletal interplay mediated by cofilin-1 and MRTF-A/SRF, promoting the dilated cardiomyopathy caused by LMNA mutations. Our findings suggest that modulating α-tubulin acetylation levels is a feasible strategy for improving cardiac function.Peer reviewe

Elevated TGF \u3b22 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes

Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF \u3b22) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF \u3b22 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF \u3b22-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF \u3b22 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF \u3b22-dependent mechanisms were also determined in laminopathic cells, where TGF \u3b22 activated AKT/mTOR phosphorylation. These data show that TGF \u3b22 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF \u3b22 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies

Emery–Dreifuss muscular dystrophy: focal point nuclear envelope

International audiencePurpose of review Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD encoding emerin and LMNA encoding A-type lamins, proteins of the nuclear envelope. In the past decade, there has been an extraordinary burst of research on the nuclear envelope. Discoveries resulting from this basic research have implications for better understanding the pathogenesis and developing treatments for EDMD. Recent findings Recent clinical research has confirmed that EDMD is one of several overlapping skeletal muscle phenotypes that can result from mutations in EMD and LMNA with dilated cardiomyopathy as a common feature. Basic research on the nuclear envelope has provided new insights into how A-type lamins and emerin function in force transmission throughout the cell, which may be particularly important in striated muscle. Much of the recent research has focused on the heart and LMNA mutations. Prevalence and outcome studies have confirmed the relative severity of cardiac disease. Robust mouse models of EDMD caused by LMNA mutations has allowed for further insight into pathogenic mechanisms and potentially beneficial therapeutic approaches. Summary Recent clinical and basic research on EDMD is gradually being translated to clinical practice and possibly novel therapies

Anomalies génétiques des laminopathies (de l'identification à l'analyse des mécanismes moléculaires et cellulaires)

Les laminopathies sont des pathologies génétiques dues à des mutations du gène LMNA codant les lamines A/C, deux protéines nucléaires. Nous avons cherché 1) à caractériser le spectre des mutations du gène LMNA dans une grande cohorte de familles atteintes de AD-EDMD, 2) à déterminer si une autre dystrophie musculaire (LGMD1B) décrite au même locus chromosomique que AD-EDMD était allélique à cette dernière, et 3) à décrypter les mécanismes moléculaires et cellulaires associées aux mutations du gène LMNA. Dans la première partie, nous avons identifié 18 nouvelles mutations dans des familles présentant une forme classique de AD-EDMD. Dans la deuxième partie, nous avons montré qu'il existait une origine commune aux deux dystrophies musculaires que sont l'AD-EDMD et la LGMD1B. La troisième partie de cette thèse a apporté des éléments importants quant aux conséquences structurales des lamines mutantes dans les cellules de patients porteurs de mutations. En conclusion, dans le contexte des laminopathies, ce travail a montré qu'il n'existe pas de phénotype particulier pour un type de mutation mais qu'il semble y avoir une relation entre le site de la mutation sur la protéine et les conséquences en terme de déstructuration de l'architecture des noyaux des cellules de patients. Une meilleure connaissance des partenaires nucléaires des lamines A/C ainsi qu'une évaluation in vivo des effets des lamines A/C mutantes sur la fonction des cellules des tissus cibles permettront de mieux comprendre les mécanismes moléculaires par lesquels les mutations LMNA conduisent au développement des laminopathies.Laminopathies are disorders due to mutation in LMNA gene encoding two nuclear proteins, lamins A and C. Our aims were 1) characterized spectrum of LMNA mutations in the first described laminopathy : AD-EDMD, 2) determine if it exist a common genetic origin to both muscular dystrophy : AD-EDMD and LGMD1B, 3) and analysed molecular and cellular consequences of LMNA mutations on patients fibroblasts. In the first part, we identified 18 new LMNA mutations in AD-EDMD patients. In the second part, we showed that AD-EDMD and LGMDB are allelic disorders. The third part bring important data concerning the role of LMNA mutations on nuclear architecture. A better understanding of nuclear partner of lamin A/C and of consequences of LMNA mutations in affected tissues, will probably help us to understand...PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

An Omics View of Emery–Dreifuss Muscular Dystrophy

International audienceRecent progress in Omics technologies has started to empower personalized healthcare development at a thorough biomolecular level. Omics have subsidized medical breakthroughs that have started to enter clinical proceedings. The use of this scientific know-how has surfaced as a way to provide a more far-reaching view of the biological mechanisms behind diseases. This review will focus on the discoveries made using Omics and the utility of these approaches for Emery-Dreifuss muscular dystrophy