The Experts below are selected from a list of 1689 Experts worldwide ranked by ideXlab platform
Gisèle Bonne - One of the best experts on this subject based on the ideXlab platform.
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cardiac manifestations of congenital lmna related Muscular Dystrophy in children three case reports and recommendations for care
Cardiology in The Young, 2017Co-Authors: Felice Heller, Gisèle Bonne, Ivana Dabaj, Jean K Mah, Jean Bergounioux, Aben Essid, Carsten G Bonnemann, Anne Rutkowski, Susana Quijanoroy, Karim WahbiAbstract:Skeletal and cardiac muscle laminopathies, caused by mutations in the lamin A/C gene, have a clinical spectrum from congenital LMNA -related Muscular Dystrophy to later-onset Emery–Dreifuss Muscular Dystrophy, limb girdle Muscular Dystrophy, and dilated cardiomyopathy. Although cardiac involvement is observed at all ages, it has only been well described in adults. We present the evolution of cardiac disease in three children with congenital Muscular Dystrophy presentation of LMNA -related Muscular Dystrophy. In this series, atrial arrhythmia was the presenting cardiac finding in all three patients. Heart failure developed up to 5 years later. Symptoms of right heart failure, including diarrhoea and peripheral oedema, preceded a rapid decline in left ventricular ejection fraction. Recommendations for cardiac surveillance and management in these patients are made.
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fhl1b interacts with lamin a c and emerin at the nuclear lamina and is misregulated in emery dreifuss Muscular Dystrophy
Journal of neuromuscular diseases, 2016Co-Authors: Gisèle Bonne, Esma Ziat, Kamel Mamchaoui, M Beuvin, I Nelson, Feriel Azibani, Simone Spuler, Anne BertrandAbstract:BACKGROUND: Emery-Dreifuss Muscular Dystrophy (EDMD) is associated with mutations in EMD and LMNA genes, encoding for the nuclear envelope proteins emerin and lamin A/C, indicating that EDMD is a nuclear envelope disease. We recently reported mutations in FHL1 gene in X-linked EDMD. FHL1 encodes FHL1A, and the two minor isoforms FHL1B and FHL1C. So far, none have been described at the nuclear envelope. OBJECTIVE: To gain insight into the pathophysiology of EDMD, we focused our attention on the poorly characterized FHL1B isoform. METHODS: The amount and the localisation of FHL1B were evaluated in control and diseased human primary myoblasts using immunofluorescence and western blotting. RESULTS: We found that in addition to a cytoplasmic localization, this isoform strongly accumulated at the nuclear envelope of primary human myoblasts, like but independently of lamin A/C and emerin. During myoblast differentiation, we observed a major reduction of FHL1B protein expression, especially in the nucleus. Interestingly, we found elevated FHL1B expression level in myoblasts from an FHL1-related EDMD patient where the FHL1 mutation only affects FHL1A, as well as in myoblasts from an LMNA-related EDMD patient. CONCLUSIONS: Altogether, the specific localization of FHL1B and its modulation in disease-patient's myoblasts confirmed FHL1-related EDMD as a nuclear envelope disease.
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inhibition of extracellular signal regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding a type lamins
Human Molecular Genetics, 2008Co-Authors: Antoine Muchir, Gisèle Bonne, Jian Shan, Stephan E Lehnart, Howard J WormanAbstract: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 LmnaH222P/H222P mice that develop cardiomyopathy with PD98059, an inhibitor of ERK activation. Systemic treatment of LmnaH222P/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 LmnaH222P/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.
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activation of mapk pathways links lmna mutations to cardiomyopathy in emery dreifuss Muscular Dystrophy
Journal of Clinical Investigation, 2007Co-Authors: Antoine Muchir, Gisèle Bonne, Paul Pavlidis, Valerie Decostre, Alan J Herron, Takuro Arimura, Howard J WormanAbstract: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.
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clinical relevance of atrial fibrillation flutter stroke pacemaker implant and heart failure in emery dreifuss Muscular Dystrophy a long term longitudinal study
Stroke, 2003Co-Authors: Giuseppe Boriani, Gisèle Bonne, Luciano Merlini, M Gallina, Daniela Toniolo, Silvia Amati, Mauro Biffi, Cristian Martignani, L Frabetti, Marco BonviciniAbstract:Background and Purpose— Emery-Dreifuss Muscular Dystrophy (EDMD) is a rare inherited disorder associated with cardiac involvement. We investigated the spectrum and relevance of the cardiac manifestations of EDMD, focusing on bradyarrhythmias and tachyarrhythmias (including atrial fibrillation/flutter), embolic stroke, and heart failure. Methods and Results— Eighteen patients (age 42.8±19.6 years) with genetically confirmed X-linked (n=10, including 3 carriers) or autosomal dominant (n=8) EDMD were followed for a period ranging from 1 to 30 years in a research center for neuroMuscular diseases and in a university cardiological department. Pacemakers were required by 10 of 18 (56%) patients for bradyarrhythmia, and related complications occurred in 3 of 10 (30%) cases. Atrial fibrillation/flutter developed in 11 of 18 (61%) patients, with atrial standstill subsequently occurring in 5 of 11 (45%) cases and embolic stroke (most often disabling) in 4 of 11 (36%). Heart failure requiring transplantation occurre...
Luciano Merlini - One of the best experts on this subject based on the ideXlab platform.
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mutation analysis of the lamin a c gene lmna among patients with different cardioMuscular phenotypes
Journal of Medical Genetics, 2003Co-Authors: M Vytopil, Luciano Merlini, Lucia Morandi, E Ricci, G Galluzzi, Dello A Russo, M Gallina, Sara Benedetti, Giuseppe Boriani, L PolitanoAbstract:Laminopathies represent a heterogeneous group of genetic disorders characterised by mutations in the LMNA gene, which encodes two lamins, A and C, by alternative splicing of the primary transcript.1 Lamins belong to the intermediate filament multigene family and form the nuclear lamina, a mesh-like structure adjacent to the nucleoplasmic side of the inner nuclear membrane.2 They interact with emerin, the proteins encoded by the gene for the X-linked (X EDMD) form of EDMD, with several nuclear envelope proteins and with chromatin. Despite their widespread distribution and their role in nuclear architecture, alterations of lamin A/C are responsible for a number of very specific but quite heterogeneous disorders. The first laminopathy was the autosomal dominant form of Emery-Dreifuss Muscular Dystrophy (EDMD), a genetic disorder characterised by the clinical triad of early onset contractures, progressive Muscular wasting and weakness with humeroperoneal distribution and cardiac conduction defects.3 The finding that emerin, an inner nuclear envelope protein, and LMNA were both involved in EDMD suggested that the lamins may represent specific and relevant factors in cardiac and skeletal muscle and that integrity of the nuclear membrane and associated structures is specifically required for muscle function. However, later on it was found that besides autosomal dominant Emery–Dreifuss Muscular Dystrophy (AD-EDMD), mutations in LMNA are responsible for six other disorders: limb girdle Muscular Dystrophy 1B, (LGMD1B),4,5 dilated cardiomyopathy with conduction system disease, (DCM-CD),6 Dunningan-type familial partial lipoDystrophy,7–9 one recessive axonal form of Charcot-Marie-Tooth neuropathy,10 mandibuloacral dysplasia,11 and Hutchinson Gilford progeria.12,13 Despite the very different phenotypic consequences of mutations in LMNA , and the quite large number of mutations identified, no genotype/phenotype correlation has been demonstrated, pointing to the role of factors other than lamins A and C in determining the different tissue specific phenotypes. …
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clinical relevance of atrial fibrillation flutter stroke pacemaker implant and heart failure in emery dreifuss Muscular Dystrophy a long term longitudinal study
Stroke, 2003Co-Authors: Giuseppe Boriani, Gisèle Bonne, Luciano Merlini, M Gallina, Daniela Toniolo, Silvia Amati, Mauro Biffi, Cristian Martignani, L Frabetti, Marco BonviciniAbstract:Background and Purpose— Emery-Dreifuss Muscular Dystrophy (EDMD) is a rare inherited disorder associated with cardiac involvement. We investigated the spectrum and relevance of the cardiac manifestations of EDMD, focusing on bradyarrhythmias and tachyarrhythmias (including atrial fibrillation/flutter), embolic stroke, and heart failure. Methods and Results— Eighteen patients (age 42.8±19.6 years) with genetically confirmed X-linked (n=10, including 3 carriers) or autosomal dominant (n=8) EDMD were followed for a period ranging from 1 to 30 years in a research center for neuroMuscular diseases and in a university cardiological department. Pacemakers were required by 10 of 18 (56%) patients for bradyarrhythmia, and related complications occurred in 3 of 10 (30%) cases. Atrial fibrillation/flutter developed in 11 of 18 (61%) patients, with atrial standstill subsequently occurring in 5 of 11 (45%) cases and embolic stroke (most often disabling) in 4 of 11 (36%). Heart failure requiring transplantation occurre...
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lamin a c mutations with lipoDystrophy cardiac abnormalities and Muscular Dystrophy
Neurology, 2002Co-Authors: A J Van Der Kooi, Gisèle Bonne, M Van Der Valk, B Eymard, D Duboc, Beril Talim, Peter Reiss, P Richard, L Demay, Luciano MerliniAbstract: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.
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clinical and molecular genetic spectrum of autosomal dominant emery dreifuss Muscular Dystrophy due to mutations of the lamin a c gene
Annals of Neurology, 2000Co-Authors: Gisèle Bonne, Antoine Muchir, Eugenio Mercuri, Andoni Urtizberea, H M Becane, D Recan, Luciano Merlini, Manfred Wehnert, R Boor, U ReunerAbstract:Emery-Dreifuss Muscular Dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (ie, 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease. Ann Neurol 2000;48:170–180
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clinical and molecular genetic spectrum of autosomal dominant emery dreifuss Muscular Dystrophy due to mutations of the lamin a c gene
Annals of Neurology, 2000Co-Authors: Gisèle Bonne, Antoine Muchir, Eugenio Mercuri, Andoni Urtizberea, H M Becane, D Recan, Luciano Merlini, Manfred Wehnert, R Boor, U ReunerAbstract:Emery-Dreifuss Muscular Dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.
Howard J Worman - One of the best experts on this subject based on the ideXlab platform.
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Reactivation of autophagy ameliorates LMNA cardiomyopathy
Autophagy, 2013Co-Authors: Jason C. Choi, Howard J WormanAbstract:Mutations in the LMNA gene, which encodes lamin A and C (lamin A/C), cause a diverse spectrum of tissue-selective diseases termed laminopathies. The most prevalent form affects striated muscles as dilated cardiomyopathy with variable skeletal muscle involvement, which includes autosomal Emery-Dreifuss Muscular Dystrophy. Mechanisms underlying the disease pathogenesis are beginning to be understood and they point toward defects in cell signaling. We therefore assessed putative signaling defects in a mouse model carrying a point mutation in Lmna (LmnaH222P/H222P) that faithfully recapitulates human Emery-Dreifuss Muscular Dystrophy. We found that AKT-mechanistic target of rapamycin (MTOR) signaling was hyperactivated in hearts of LmnaH222P/H222P mice and that reducing MTOR activity by pharmacological intervention ameliorated cardiomyopathy. Given the central role of MTOR in regulating autophagy, we assessed fasting-induced autophagic responses and found that they were impaired in hearts of these mice. Moreo...
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inhibition of extracellular signal regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding a type lamins
Human Molecular Genetics, 2008Co-Authors: Antoine Muchir, Gisèle Bonne, Jian Shan, Stephan E Lehnart, Howard J WormanAbstract: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 LmnaH222P/H222P mice that develop cardiomyopathy with PD98059, an inhibitor of ERK activation. Systemic treatment of LmnaH222P/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 LmnaH222P/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.
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activation of mapk pathways links lmna mutations to cardiomyopathy in emery dreifuss Muscular Dystrophy
Journal of Clinical Investigation, 2007Co-Authors: Antoine Muchir, Gisèle Bonne, Paul Pavlidis, Valerie Decostre, Alan J Herron, Takuro Arimura, Howard J WormanAbstract: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.
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pathology and nuclear abnormalities in hearts of transgenic mice expressing m371k lamin a encoded by an lmna mutation causing emery dreifuss Muscular Dystrophy
Human Molecular Genetics, 2006Co-Authors: Yuexia Wang, Alan J Herron, Howard J WormanAbstract:Mutations in LMNA, which encodes nuclear lamins A and C, cause a broad range of diseases, including autosomal dominant Emery-Dreifuss Muscular Dystrophy (EDMD) and related disorders with a predominant cardiomyopathy. Homozygous Lmna model "knock-in" and null mice develop cardiomyopathy, whereas heterozygous mice do not. Overexpression of lamin A mutants that cause cardiomyopathy in cultured cells induces morphological abnormalities in the nuclear envelope and lamina; however, effects on tissue and organ pathology have not been determined. We used the heart-selective alpha-myosin heavy chain promoter to drive expression in transgenic mice of human wild-type and M371K lamin A, which causes EDMD. Mice expressing M371K lamin A were born at approximately 0.07 of the expected frequency and those born typically died at 2-7 weeks of age. Histological analysis showed increased eosinophilia and fragmentation of cardiomyofibrils, nuclear pyknosis and edema without fibrosis or significant inflammation, indicative of acute or subacute injury. Mice expressing human wild-type lamin A were born at only slightly less than the expected frequency and had normal life spans. Confocal immunofluorescence microscopy demonstrated abnormal nuclear envelopes with intranuclear foci of lamins in cardiac cells expressing M371K lamin A. Electron microscopy revealed extensively convoluted nuclear envelopes, intranuclear inclusions and chromatin clumps in cardiomyocyte nuclei. These results demonstrate that expression of a lamin A mutant that induces alterations in nuclear morphology can cause tissue and organ damage in mice with a normal complement of wild-type lamins.
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the ig like structure of the c terminal domain of lamin a c mutated in Muscular dystrophies cardiomyopathy and partial lipoDystrophy
Structure, 2002Co-Authors: Isabelle Krimm, Jean-claude Courvalin, Gisèle Bonne, Howard J Worman, Cecilia Ostlund, Bernard Gilquin, Joel Couprie, Paul Hossenlopp, Jeanpaul Mornon, Sophie ZinnjustinAbstract:Abstract 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.
U Reuner - One of the best experts on this subject based on the ideXlab platform.
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clinical and molecular genetic spectrum of autosomal dominant emery dreifuss Muscular Dystrophy due to mutations of the lamin a c gene
Annals of Neurology, 2000Co-Authors: Gisèle Bonne, Antoine Muchir, Eugenio Mercuri, Andoni Urtizberea, H M Becane, D Recan, Luciano Merlini, Manfred Wehnert, R Boor, U ReunerAbstract:Emery-Dreifuss Muscular Dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (ie, 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease. Ann Neurol 2000;48:170–180
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clinical and molecular genetic spectrum of autosomal dominant emery dreifuss Muscular Dystrophy due to mutations of the lamin a c gene
Annals of Neurology, 2000Co-Authors: Gisèle Bonne, Antoine Muchir, Eugenio Mercuri, Andoni Urtizberea, H M Becane, D Recan, Luciano Merlini, Manfred Wehnert, R Boor, U ReunerAbstract:Emery-Dreifuss Muscular Dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.
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direct molecular genetic diagnosis and heterozygote identification in x linked emery dreifuss Muscular Dystrophy by heteroduplex analysis
Disease Markers, 1997Co-Authors: K Wulff, U Reuner, U Ebener, C S Wehnert, P A Ward, W Hiebsch, F H Herrmann, Manfred WehnertAbstract:X-linked Emery-Dreifuss Muscular Dystrophy (EMD) is a very rare, relatively benign muscle disorder. The disease is associated with potentially lethal cardiac arrhythmias in affected males and some heterozygous females. X-linked EMD can be genetically distinguished from phenotypically similar autosomal EMD. Heterogenic mutations are identified as the cause of X-linked EMD. We introduced heteroduplex analysis to follow the segregation of heterogenic emerin gene mutations in the families of six unrelated EMD patients. Heteroduplex analysis was proved to be a simple, fast and reliable tool for direct molecular genetic diagnosis of EMD in male patients and identification of heterozygotes even in families where affected males are not available as index cases.
Manfred Wehnert - One of the best experts on this subject based on the ideXlab platform.
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linc complex and human genetic Muscular disease
eLS, 2012Co-Authors: Manfred Wehnert, Peter MeinkeAbstract:The linker of nucleoskeleton and cytoskeleton (LiNC) complex is a proposed mechanical link tethering the nucleo- and cytoskeleton via the nuclear envelope (NE). The LiNC components emerin, lamin A/C, SUN1, SUN2, nesprin 1 and nesprin 2 interact with each other at the NE and also with other binding partners including actin filaments and B-type lamins. Besides the mechanostructural functions, cell- or tissue-specific LiNC complexes are also involved in signalling pathways and gene regulation. Emerin was the first LiNC component associated with a human disease, namely Emery–Dreifuss Muscular Dystrophy (EDMD). Later on, other components of a hypothetically muscle-specific LiNC complex, such as lamins A/C and small muscle-specific isoforms of nesprin 1 and nesprin 2, were found to be associated with EDMD, reflecting a genetic heterogeneity that has not been resolved so far. Only approximately 47% of the EDMD patients can be linked to genes of LiNC and non-LiNC components, probably interacting with muscle-specific LiNC(s) involved in the pathology of Muscular disorders. Key Concepts: Linker of nucleoskeleton and cytoskeleton (LiNC) complexes are tethering the nucleo- and cytoskeleton via the nuclear envelope. The inhibition of LiNC components results in changes of the biomechanical behaviour of contractile cells. Mutations in genes encoding muscle-specific LiNC components lead to a variety of inherited human Muscular disorders, in particular Emery–Dreifuss Muscular Dystrophy. The wide phenotypic variability of LiNC-associated Muscular diseases can be explained by digenic inheritance. The association of LiNC and LiNC-related components with human disease helps to resolve genetic heterogeneity and clinical variability and provides tools to understand their functions within the cell as well. Keywords: LiNC complex; Emery–Dreifuss Muscular Dystrophy; neuroMuscular disorders; lamin A/C; emerin; nesprin 1; nesprin 2; SUN1; SUN2
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linc complex alterations in dmd and edmd cmt fibroblasts
European Journal of Cell Biology, 2012Co-Authors: Surayya Taranum, Manfred Wehnert, Peter Meinke, Liu Yang, Eva Vaylann, Sabu Abraham, Sascha Neumann, Iakowos Karakesisoglou, Angelika A. NoegelAbstract:Emery-Dreifuss Muscular Dystrophy (EDMD) is a late onset-disease characterized by skeletal muscle wasting and heart defects with associated risk of sudden death. The autosomal dominant form of the disease is caused by mutations in the LMNA gene encoding LaminA and C, the X-linked form results from mutations in the gene encoding the inner nuclear membrane protein Emerin (STA). Both Emerin and LaminA/C interact with the nuclear envelope proteins Nesprin-1 and -2 and mutations in genes encoding C-terminal isoforms of Nesprin-1 and -2 have also been implicated in EDMD. Here we analyse primary fibroblasts from patients affected by either Duchenne Muscular Dystrophy (DMD) or Emery-Dreifuss Muscular Dystrophy/Charcot-Marie-Tooth syndrome (EDMD/CMT) that in addition to the disease causing mutations harbour mutations in the Nesprin-1 gene and in the SUN1 and SUN2 gene, respectively. SUN proteins together with the Nesprins form the core of the LINC complex which connects the nucleus with the cytoskeleton. The mutations are accompanied by changes in cell adhesion, cell migration, senescence, and stress response, as well as in nuclear shape and nuclear envelope composition which are changes characteristic for laminopathies. Our results point to a potential influence of mutations in components of the LINC complex on the clinical outcome and the molecular pathology in the patients.
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p s143f mutation in lamin a c a new phenotype combining myopathy and progeria
Annals of Neurology, 2005Co-Authors: Manfred Wehnert, Christina Wasner, Anja Feuer, Janbernd Kirschner, Thomas Brune, Jonas Denecke, Thorsten Marquardt, Uwepeter Ketelsen, Peter WieackerAbstract:We report a young girl with a phenotype combining early-onset myopathy and a progeria. She had myopathy and marked axial weakness during the first year of life; progeroid features, including growth failure, sclerodermatous skin changes, and osteolytic lesions, developed later. We identified the underlying cause to be a hitherto unreported de novo missense mutation in the LMNA gene (S143F) encoding the nuclear envelope proteins lamins A and C. Although LMNA mutations have been known to cause Hutchinson-Gilford progeria syndrome and Emery-Dreifuss Muscular Dystrophy, this is the first report of a patient combining features of these two phenotypes because of a single mutation in LMNA.
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clinical and molecular genetic spectrum of autosomal dominant emery dreifuss Muscular Dystrophy due to mutations of the lamin a c gene
Annals of Neurology, 2000Co-Authors: Gisèle Bonne, Antoine Muchir, Eugenio Mercuri, Andoni Urtizberea, H M Becane, D Recan, Luciano Merlini, Manfred Wehnert, R Boor, U ReunerAbstract:Emery-Dreifuss Muscular Dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (ie, 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease. Ann Neurol 2000;48:170–180
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clinical and molecular genetic spectrum of autosomal dominant emery dreifuss Muscular Dystrophy due to mutations of the lamin a c gene
Annals of Neurology, 2000Co-Authors: Gisèle Bonne, Antoine Muchir, Eugenio Mercuri, Andoni Urtizberea, H M Becane, D Recan, Luciano Merlini, Manfred Wehnert, R Boor, U ReunerAbstract:Emery-Dreifuss Muscular Dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.