Search

LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both harboring the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5, pointing to a developmental origin of the disease. Using mouse ESCs, we demonstrated that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in LmnaH222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylated H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy.

Mutations in the lamin A/C gene (LMNA) cause an autosomal dominant inherited form of dilated cardiomyopathy associated with cardiac conduction disease (hereafter referred to as LMNA cardiomyopathy). Compared with other forms of dilated cardiomyopathy, mutations in LMNA are responsible for a more aggressive clinical course owing to a high rate of malignant ventricular arrhythmias. Gap junctions are intercellular channels that allow direct communication between neighboring cells, which are involved in electrical impulse propagation and coordinated contraction of the heart. For gap junctions to properly control electrical synchronization in the heart, connexin-based hemichannels must be correctly targeted to intercalated discs, Cx43 being the major connexin in the working myocytes. We here showed an altered distribution of Cx43 in a mouse model of LMNA cardiomyopathy. However, little is known on the molecular mechanisms of Cx43 remodeling in pathological context. We now show that microtubule cytoskeleton alteration and decreased acetylation of α-tubulin lead to remodeling of Cx43 in LMNA cardiomyopathy, which alters the correct communication between cardiomyocytes, ultimately leading to electrical conduction disturbances. Preventing or reversing this process could offer a strategy to repair damaged heart. Stabilization of microtubule cytoskeleton using Paclitaxel improved intraventricular conduction defects. These results indicate that microtubule cytoskeleton contributes to the pathogenesis of LMNA cardiomyopathy and that drugs stabilizing the microtubule may be beneficial for patients., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation., Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]., Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach., Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscle and electrical dysfunction of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for heart function. Biosynthesis of NAD+ from vitamin B3 (known as salvage pathways) is the primary source of NAD+. We showed here that NAD+ salvage pathway was altered in the heart of mouse and human carrying LMNA mutation, leading to an alteration of one of NAD+ co-substrate enzymes, PARP-1. Oral administration of nicotinamide riboside, a natural NAD+ precursor and a pyridine-nucleoside form of vitamin B3, leads to a marked improvement of the NAD+ cellular content, an increase of PARylation of cardiac proteins and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our results provide mechanistic and therapeutic insights into dilated cardiomyopathy caused by LMNA mutations.

Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-β/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To identify the genetic defects present in 3 families with muscular dystrophy, contractures, and calpain 3 deficiency., Methods: We performed targeted exome sequencing on one patient presenting a deficiency in calpain 3 on Western blot but for which mutations in the gene had been excluded. The identification of a homozygous truncating mutation in the M-line part of titin prompted us to sequence this region in 2 additional patients presenting similar clinical and biochemical characteristics., Results: The 3 patients shared similar features: coexistence of limb-girdle weakness and early-onset diffuse joint contractures without cardiomyopathy. The biopsies showed rimmed vacuoles, a dystrophic pattern, and secondary reduction in calpain 3. We identified a novel homozygous mutation in the exon Mex3 of the TTN gene in the first patient. At protein level, this mutation introduces a stop codon at the level of Mex3. Interestingly, we identified truncating mutations in both alleles in the same region of the TTN gene in patients from 2 additional families. Molecular protein analyses confirm loss of the C-ter part of titin., Conclusions: Our study broadens the phenotype of titinopathies with the report of a new clinical entity with prominent contractures and no cardiac abnormality and where the recessive mutations lead to truncation of the M-line titin and secondary calpain 3 deficiency., (© 2015 American Academy of Neurology.)

Background: Dystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association., Methods: We used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein., Results: We report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in TOR1AIP1. The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine. TOR1AIP1 encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia. In vitro studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms., Conclusions and Relevance: The pathogenic role of TOR1AIP1 mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the TOR1AIP1 nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations.

Lamins A and C, encoded by LMNA, are constituent of the nuclear lamina, a meshwork of proteins underneath the nuclear envelope first described as scaffolding proteins of the nucleus. Since the discovery of LMNA mutations in highly heterogeneous human disorders (including cardiac and muscular dystrophies, lipodystrophies and progeria), the number of functions described for lamin A/C has expanded. Lamin A/C is notably involved in the regulation of chromatin structure and gene transcription, and in the resistance of cells to mechanical stress. This review focuses on studies performed on knock-out and knock-in Lmna mouse models, which have led to decipher some of the lamin A/C functions in striated muscles and to the first preclinical trials of pharmaceutical therapies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aims: The transcription factor Islet-1 (ISL1) is a marker of cardiovascular progenitors and is essential for mammalian cardiogenesis. An ISL1 haplotype has recently been associated with congenital heart disease. In this study we evaluated whether ISL1 variants are associated with hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), or with Emery-Dreifuss muscular dystrophy (EDMD)., Methods and Results: The six exon and intron boundaries of ISL1 were screened for genetic variants in a cohort of 454 index cases. Eleven exonic variants were identified in HCM, DCM, ARVC, and/or EDMD. Out of the five novel variants, two are located in the 5'-untranslated region, two are silent (p.Arg171Arg and p.Asn189Asn), and one is a missense (p.Asn252Ser). The latter was identified in the homozygous state in one DCM patient, and in the heterozygous state in 11 relatives, who did not present with DCM but often with cardiovascular features. This variant was found in one HCM patient also carrying a MYH7 mutation and in 3/96 North-African Caucasian control individuals, but was absent in 138 European Caucasian control individuals. We investigated the effect of the ISL1 wild type and p.Asn252Ser mutant on myocyte enhancer factor 2C (Mef2c) promoter activity, an established ISL1 target. Mef2c promoter activity was ∼4-fold higher in the presence of wild-type and ∼6-fold higher in the presence of mutant ISL1 in both HEK and CHO cells., Conclusion: This study describes a new gain-of-function p.Asn252Ser variant in the human ISL1 gene, which could potentially lead to greater activation of downstream targets involved in cardiac development, dilation, and hypertrophy.

Mutations in LMNA, which encodes A-type nuclear lamins, cause disorders of striated muscle that have as a common feature dilated cardiomyopathy. We have demonstrated an abnormal activation of both the extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal kinase (JNK) branches of the mitogen-activated protein kinase signaling cascade in hearts from Lmna(H222P/H222P) mice that develop dilated cardiomyopathy. We previously showed that pharmacological inhibition of cardiac ERK signaling in these mice delayed the development of left ventricle dilatation and deterioration in ejection fraction. In the present study, we treated Lmna(H222P/H222P) mice with SP600125, an inhibitor of JNK signalling. Systemic treatment with SP600125 inhibited JNK phosphorylation, with no detectable effect on ERK. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in the architecture of the sarcomere that occurred in placebo-treated mice. Furthermore, treatment with SP600125 significantly delayed the development of left ventricular dilatation and prevented decreases in cardiac ejection fraction and fibrosis. These results demonstrate a role for JNK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof-of-principle for JNK inhibition as a novel therapeutic option to prevent or delay the cardiomyopathy in humans with mutations in LMNA., (Copyright 2010 Elsevier B.V. All rights reserved.)

Autosomal Emery-Dreifuss muscular dystrophy and related disorders with dilated cardiomyopathy and variable skeletal muscle involvement are caused by mutations in LMNA, which encodes A-type nuclear lamins. How alterations in A-type lamins, intermediate filament proteins of the nuclear envelope expressed in most differentiated somatic cells, cause cardiomyopathy is only poorly understood. We demonstrated previously abnormal activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) signaling cascade in hearts of Lmna H222P 'knock in' mice, a model of autosomal Emery-Dreifuss muscular dystrophy. We therefore treated Lmna(H222P/H222P) mice that develop cardiomyopathy with PD98059, an inhibitor of ERK activation. Systemic treatment of Lmna(H222P/H222P) mice with PD98059 inhibited ERK phosphorylation and blocked the activation of downstream genes in heart. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere organization that occurred in placebo-treated mice. Histological analysis and echocardiography demonstrated that treatment with PD98059 delayed the development of left ventricular dilatation. PD98059-treated Lmna(H222P/H222P) mice had normal cardiac ejection fractions assessed by echocardiography when placebo-treated mice had a 30% decrease. These results emphasize the role of ERK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof of principle for ERK inhibition as a therapeutic option to prevent or delay heart failure in humans with Emery-Dreifuss muscular dystrophy and related disorders caused by mutations in LMNA.

Mutations in LMNA, which encodes nuclear Lamins A and C cause diseases affecting various organs, including the heart. We have determined the effects of an Lmna H222P mutation on signaling pathways involved in the development of cardiomyopathy in a knockin mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy. Analysis of genome-wide expression profiles in hearts using Affymetrix GeneChips showed statistically significant differences in expression of genes in the MAPK pathways at the incipience of the development of clinical disease. Using real-time PCR, we showed that activation of MAPK pathways preceded clinical signs or detectable molecular markers of cardiomyopathy. In heart tissue and isolated cardiomyocytes, there was activation of MAPK cascades and downstream targets, implicated previously in the pathogenesis of cardiomyopathy. Expression of H222P Lamin A in cultured cells activated MAPKs and downstream target genes. Activation of MAPK signaling by mutant A-type lamins could be a cornerstone in the development of heart disease in autosomal dominant Emery-Dreifuss muscular dystrophy.

Background: Emery-Dreifuss muscular dystrophy is a genetically heterogeneous form of muscular dystrophy. One form is inherited in an X-linked fashion and is secondary to mutations in the gene encoding the nuclear protein emerin. A more common variant is inherited in an autosomal dominant way (EDMD2) due to mutations affecting the nuclear lamina protein lamin A/C. Typical features of both conditions are relatively mild skeletal muscle weakness, but cardiac involvement develops almost invariably by adult age, including conduction defects, arrhythmias and cardiomyopathy. Thus, early detection of cardiac abnormalities may be important for planning early therapeutic intervention., Aim: In this study, we hypothesized that early myocardial dysfunction can be detected by tissue Doppler echocardiography and CMR in unselected patients with the autosomal dominant form of Emery-Dreifuss muscular dystrophy. This would suggest that fibrosis could be implicated in the pathogenesis of cardiac dysfunction in EDMD2., Methods: Eight consecutive patients with genetically proven EDMD2 without pacemakers were enrolled in the study and compared to eight age-matched controls. All patients and controls first underwent a comprehensive echocardiographic-Doppler examination, followed by measurement of mitral annular velocities using pulsed tissue Doppler. Color M-mode tissue images were recorded from the parasternal long axis projections to derive Myocardial Velocity Gradients (MVG). Subsequently, all subjects underwent cardiovascular magnetic resonance (CMR) imaging for function, intrinsic myocardial tissue contrast using T1 and T2 weighted spin echo (TSE) for fat deposition and extrinsic contrast (Gadolinium-DTPA late fibrosis imaging). Strain measurements, using harmonic phase imaging (HARP) tagging were also derived., Results: Cavity dimensions LV mass and fractional shortening were similar between patients and controls. The overall body mass index was less in patients than in controls (14.5 +/- 1.4 vs. 18.1 +/- 2.4 g/m2, p < 0.002). While systolic MVG were similar between groups, the early diastolic MVG was lower in patients than in controls (4 +/- 1.2 s-1 vs. 7.1 +/- 2.7, p < 0.02). On CMR, LA and LV, RV volumes were similar between patients and controls. CMR strain patterns, however, showed a significant reduction in inferior wall contractility in patients compared to controls (-0.06 +/- 0.02 vs -0.09 +/- 0.03, p < 0.05). No patient showed late gadolinium enhancement., Conclusion: Patients with EDMD2 have abnormal left ventricular function prior to developing any cardiac symptoms. The absence of myocardial fibrosis, however, by CMR suggests that this functional abnormality may not be secondary to scarring but could precede it. Tissue Doppler echocardiography and CMR are sensitive methods of assessing the presence of myocardial dysfunction prior to the development of any cardiovascular symptoms.

Mutations in LMNA, the gene that encodes nuclear lamins A and C, cause up to eight different diseases collectively referred to as "laminopathies." These diseases affect striated muscle, adipose tissue, peripheral nerve, and bone, or cause features of premature aging. We investigated the consequences of LMNA mutations on nuclear architecture in skin fibroblasts from 13 patients with different laminopathies. Western-blotting showed that none of the mutations examined led to a decrease in cellular levels of lamin A or C. Regardless of the disease, we observed honeycomb nuclear structures and nuclear envelope blebs in cells examined by immunofluorescence microscopy. Concentrated foci of lamin A/C in the nucleoplasm were also observed. Only mutations in the head and tail domains of lamins A and C significantly altered the nuclear architecture of patient fibroblasts. These results confirm that mutations in lamins A and C may lead to a weakening of a structural support network in the nuclear envelope in fibroblasts and that nuclear architecture changes depend upon the location of the mutation in different domains of lamin A/C.

Mutations in the lamin A/C gene are found in Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy with cardiac conduction disturbances, dilated cardiomyopathy with conduction system disease, and familial partial lipodystrophy. Cases with lamin A/C mutations presenting with lipodystrophy in combination with cardiac and/or skeletal muscle abnormalities are described.

Lamins are nuclear intermediate filaments that, together with lamin-associated proteins, maintain nuclear shape and provide a structural support for chromosomes and replicating DNA. We have determined the solution structure of the human lamin A/C C-terminal globular domain which contains specific mutations causing four different heritable diseases. This domain encompasses residues 430-545 and adopts an Ig-like fold of type s. We have also characterized by NMR and circular dichroism the structure and thermostability of three mutants, R453W and R482W/Q, corresponding to "hot spots" causing Emery-Dreifuss muscular dystrophy and Dunnigan-type lipodystrophy, respectively. Our structure determination and mutant analyses clearly show that the consequences of the mutations causing muscle-specific diseases or lipodystrophy are different at the molecular level.

We studied 54 living relatives from a large French kindred, among which 17 members presented with a cardiomyopathy transmitted on an autosomal dominant mode. Five of these individuals had clinical manifestations of muscle disease phenotypically consistent with Emery-Dreifuss muscular dystrophy. Genetic analysis of this kindred had demonstrated a nonsense mutation in the LMNA gene located on chromosome 1q11-q23. This gene encodes lamins A and C, proteins of the nuclear lamina located on the inner face of the nuclear envelope. We retrospectively determined the cause of death of 15 deceased family members, 8 of whom had died suddenly, 2 as a first and single manifestation of the disease. The six other cases had histories of arrhythmias and left ventricular dysfunction before dying suddenly, and three of them died despite the prior implantation of a permanent pacemaker. The mean age of onset of cardiac symptoms among affected living family members was 33 years (range 15-47 years), and the first symptoms were due to marked atrioventricular conduction defects or sinus dysfunction, requiring the implantation of permanent pacemakers in seven cases. Myocardial dysfunction accompanied by ventricular arrhythmias developed rapidly in the course of the disease and resulted in severe dilated cardiomyopathy requiring cardiac transplantation in three cases. In conclusion, in patients presenting a life-threatening familial or sporadic cardiac restricted phenotype similar to that described here, mutations in the lamins A and C gene should be looked for. In the genotypically affected individuals, cardiological and electrophysiological follow-up should be performed to prevent sudden death that could occur rapidly in the evolution of such disease.

Details the mutational analysis of lamin A/C gene (LMNA) in a large white population of patients affected by dilated cardiomyopathy (DCM) with or without associated symptoms. Missense mutation identified in a family with early atrial fibrillation and a previously described mutation in another family with a quadriceps myopathy associated with DCM.

Purpose. Familial cardiomyopathies are caused by genetic mutations that induce accumulation of misfolded proteins with consequent cardiomyocyte death and maladaptive cardiac remodelling. Molecular chaperones are a family of proteins devoted to prevent accumulation of misfolded proteins by promoting either their refolding or degradation via the ubiquitin-proteasome or the autophagosome systems and can thus represent a potential mean to treat familial cardiomyopathies.Methods. Melusin is a muscle specific chaperone protein whose overexpression effectively prevents maladaptive cardiac remodeling and heart failure both in pressure overload and myocardial infarct mouse models. In this study we use in vivo gene delivery with cardiotropic adeno associated virus 9 vector to induce to increase melusin expression in the heart of mice carrying H222P Lamin A mutation mimicking human Emery-Dreifuss familial cardiomyopathy. Mutant male mice develop spontaneous dilated cardiomyopathy from 4 months of age and die within 10-12 months of age.Results. Homozygous mutant mice were injected with AAV9-Melusin (I.V. injection of 1012 viral particles/mouse) either at 1 month of age before development of the cardiomyopathy or at 4 months when cardiomyopathy was already present to test for both preventive and therapeutic activity. Cardiac function was monitored by echocardiography for the following months. While untreated mice progressively developed left ventricle dilation and reduced contractility (FS%), mice injected with AAV9-Melusin retained physiological level of contractility and were protected toward LV dilation. Ten months after the treatment, 40% of mutant mice died, while 100% of melusin-treated mice were alive. A second group of mutant male mice was injected with AAV9-melusin at 4 months of age when the cardiomyopathy was already detectable. Interestingly melusin prevented the deterioration of contractility in the following 6 months and significantly reduced mortality.Conclusions These data indicate that melusin chaperone overexpression can effectively delay the onset of Emery-Dreifuss cardiomyopathy as well as arrest the progression of the already established pathology. [ABSTRACT FROM AUTHOR]

La dystrophie musculaire d’Emery-Dreifuss (EDMD) est une pathologie associant une atteinte des muscles squelettiques, des rétractions tendineuses et une cardiomyopathie dilatée (DCM) avec troubles rythmiques et/ou conductifs. La forme autosomique dominante d’EDMD est liée à des mutations du gène LMNA codant les lamines A/C, protéines de l’enveloppe nucléaire. Les mécanismes par lesquels les mutations de ces protéines ubiquitaires conduisent à une atteinte spécifique du muscle strié restent à élucider. Pour comprendre la physiopathologie associée à ces mutations, notre équipe a créé un modèle murin reproduisant une mutation responsable d’une forme sévère d’EDMD : le modèle knock-in LmnadelK32. Les souris hétérozygotes LmnadelK32/+ présentent une dysfunction contractile cardiaque lentement progressive, évoluant en DCM conduisant au décès entre l’âge de 250 et 500 jours. Elles ne montrent pas de troubles rythmiques ni conductifs. Au stade terminal, le ventricule gauche présente une fibrose endocardique et une légère accumulation de lipides et de glycogène. L’analyse protéique du tissu cardiaque n’indique pas de différence d’expression des lamines A/C chez les souris LmnadelK32/+ comparées à leurs contrôles wild-types. Par contre, une augmentation significative de l’expression de tubuline a été mise en évidence chez les souris LmnadelK32/+ symptomatiques âgées de 400J. Enfin, la voie de signalisation ERK1 est activée chez les souris LmnadelK32/+ de 70J, encore asymptomatiques, malgré une diminution du niveau d’expression protéique de ERK1. Cependant, cette activation et cette diminution d’expression ne sont pas retrouvées chez les animaux symptomatiques. En conclusion, la souris LmnadelK32/+ présente une DCM et constitue le premier modèle murin autosomique dominant d’EDMD muté dans le gène Lmna. Nos premiers résultats permettent de formuler des hypothèses physiopathologiques à l’origine de la DCM : 1) la mutation LmnadelK32, localisée dans le domaine de dimérisation des lamines A/C, induirait une fragilisation de l’enveloppe nucléaire et un remodelage compensatoire du cytosquelette microtubulaire qui pourrait retentir sur les propriétés contractiles des cardiomyocytes ; 2) l’activation de la signalisation ERK1 précède le développement de la DCM. Il reste à déterminer si l’activation précoce de ERK1 joue un rôle protecteur ou inducteur de la DCM. [Copyright &y& Elsevier]

Abstract: Bethlem myopathy and Ullrich congenital muscular dystrophy are part of the heterogeneous group of collagen VI-related muscle disorders. They are caused by mutations in collagen VI (ColVI) genes (COL6A1, COL6A2, and COL6A3) while LMNA mutations cause autosomal dominant Emery-Dreifuss muscular dystrophy. A muscular dystrophy pattern and contractures are found in all three conditions, making differential diagnosis difficult especially in young patients when cardiomyopathy is absent. We retrospectively assessed upper and lower limb muscle CT scans in 14 Bethlem/Ullrich patients and 13 Emery-Dreifuss patients with identified mutations. CT was able to differentiate Emery-Dreifuss muscular dystrophy from ColVI-related myopathies in selected thigh muscles and to a lesser extent calves muscles: rectus femoris fatty infiltration was selectively present in Bethlem/Ullrich patients while posterior thigh muscles infiltration was more prominently found in Emery-Dreifuss patients. A more severe fatty infiltration particularly in the leg posterior compartment was found in the Emery-Dreifuss group. [ABSTRACT FROM AUTHOR]