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Corrado Angelini - One of the best experts on this subject based on the ideXlab platform.
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Limb-Girdle Muscular Dystrophy Type 2E
Genetic Neuromuscular Disorders, 2014Co-Authors: Corrado AngeliniAbstract:This disorder has been recognized to be due to mutations in the SGCB gene encoding the Beta-Sarcoglycan protein subunit (Table 13.1), which results in biochemical deficiency of the entire Sarcoglycan protein complex. This primary defect gives rise to a severe clinical phenotype of muscular dystrophy, which is usually associated with severe dilated cardiomyopathy. While alpha- and gamma-Sarcoglycan proteins are expressed almost exclusively in striated muscle, Beta- and delta-Sarcoglycans are expressed additionally in smooth muscle and coronary vessels, suggesting that in primary Beta- and delta-Sarcoglycanopathies a dysfunction of vascular function and nNOS activity may be involved in the pathogenesis of the disease.
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Limb-Girdle Muscular Dystrophy Type 2E: Clinical, Genetic and Histopathological Features of 27 European Patients (P07.031)
Neurology, 2013Co-Authors: Claudio Semplicini, Corrado Angelini, Julia R. Dahlqvist, Bruno Eymard, Luca Bello, Nanna Witting, Tanya Stojkovic, Morten Duno, John Vissing, Elena PegoraroAbstract:OBJECTIVE: To determine the clinical characteristics of limb-girdle muscular dystrophy 2E (LGMD2E), and to investigate whether genetic or histopathological features can predict the phenotype. BACKGROUND: LGMD2E is a rare muscular dystrophy due to the mutations in Beta-Sarcoglycan gene.LGMD2E is usually severe, but that has only been reported in few case studies. DESIGN/METHODS: All LGMD2E patients followed at three European neuromuscular centres were included. The past medical history was collected, and disease course was evaluated by specific questionnaires. Molecular analysis of SGCB gene and histopathological features of muscle biopsies were reviewed.A specific evaluation protocol was created, including clinical-instrumental quantitative evaluation of motor, respiratory and cardiac function. RESULTS: 27 patients (15M-12F,9-66yrs) from 22 families were included. Two populations could be identified according to disease severity: a severe form (n=17) with onset CONCLUSIONS: This study reports the largest series of LGMD2E patients to date, demonstrates the phenotypic spectrum of LGMD2E, and identifies two mutations predictive of the disease course. The LGMD2E phenotype is associated with a high incidence of cardiomyopathy and less frequent respiratory insufficiency. Disclosure: Dr. Semplicini has nothing to disclose. Dr. Dahlqvist has nothing to disclose. Dr. Eymard has received personal compensation for activities with Biomarin. Dr. Bello has nothing to disclose. Dr. Witting has nothing to disclose. Dr. Stojkovic has nothing to disclose. Dr. Angelini has received personal compensation for activities with Genzyme as a member of the Advisory Board. Dr. Duno has nothing to disclose. Dr. Leturcq has nothing to disclose. Dr. Vissing has received personal compensation for activities with Genzyme Corporation. Dr. Pegoraro has received personal compensation for activiteis with BioMarin Pharmaceutical Inc. and MEDA Pharmaceuticals Inc. Dr. Laforet has received honorarium from Genzyme company and intitution grants.
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Decorin and biglycan expression is differentially altered in several muscular dystrophies.
Brain : a journal of neurology, 2005Co-Authors: Simona Zanotti, Corrado Angelini, Elena Pegoraro, Tiziana Negri, Pia Bernasconi, Cristina Cappelletti, Eleonora Canioni, Claudia Di Blasi, Patrizia Ciscato, Alessandro PrelleAbstract:Biglycan and decorin are small extracellular proteoglycans that interact with cytokines, whose activity they may modulate, and with matrix proteins, particularly collagens. To better understand their role in muscle fibrosis, we investigated expression of decorin and biglycan transcripts and protein in muscle of several forms of muscular dystrophy, and also expression of perlecan, an extracellular proteoglycan unrelated to collagen deposition. In Duchenne muscular dystrophy (DMD) and LAMA2-mutated congenital muscular dystrophy (MDC1A) we also quantitated transcript levels of the profibrotic cytokine TGF-Beta1. We examined muscle biopsies from nine DMD patients, aged 2-8 years; 14 BMD (Becker muscular dystrophy) patients (nine aged 1-5 years; five aged 30-37 years); four MDC1A patients (aged 2-7 years); six dysferlin-deficient patients (aged 19-53 years) with mutation ascertained in two, and normal expression of proteins related to limb girdle muscular dystrophies in the others; 10 Sarcoglycan-deficient patients: seven with alpha-Sarcoglycan mutation, two with Beta-Sarcoglycan mutation and one with gamma-Sarcoglycan mutation (five aged 8-15 years; five aged 26-43 years); and nine children (aged 1-6 years) and 12 adults (aged 16-61 years) suspected of neuromuscular disease, but who had normal muscle on biopsy. Biglycan mRNA levels varied in DMD and MDC1A depending on the quantitation method, but were upregulated in BMD, Sarcoglycanopathies and dysferlinopathy. Decorin mRNA was significantly downregulated in DMD and MDC1A, whereas TGF-Beta1 was significantly upregulated. Decorin mRNA was normal in paediatric BMD, but upregulated in adult BMD, Sarcoglycanopathies and dysferlinopathy. Perlecan transcript levels were similar to those of age-matched controls in all disease groups. By immunohistochemistry, decorin and biglycan were mainly localized in muscle connective tissue; their presence increased in relation to increased fibrosis in all dystrophic muscle. By visual inspection, decorin bands on immunoblot did not differ from those of age-matched controls in all patient groups. However, when the intensity of the bands was quantitated against vimentin and normalized against sarcomeric actin, in DMD and MDC1A the ratio of band intensities was significantly lower than in age-matched controls. Variations in the transcript and protein levels of these proteoglycans in different muscular dystrophies probably reflect the variable disruption of extracellular matrix organization that occurs in these diseases. The significantly lowered decorin levels in DMD and MDC1A may be related to the increased TGF-Beta1 levels, suggesting a therapeutic role of decorin in these severe dystrophies.
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Genetic epidemiology of muscular dystrophies resulting from Sarcoglycan gene mutations.
Journal of medical genetics, 1997Co-Authors: Marina Fanin, David Duggan, Eric P. Hoffman, M.l. Mostacciuolo, F. Martinello, M. P. Freda, Gianni Sorarù, Carlo P. Trevisan, Corrado AngeliniAbstract:BACKGROUND: The autosomal recessive limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscle diseases characterised by progressive proximal limb muscle weakness. Six different loci have been mapped and pathogenetic mutations in the genes encoding the Sarcoglycan complex components (alpha-, Beta-, gamma-, and delta-Sarcoglycan) have been documented. LGMD patients affected with primary "Sarcoglycanopathies" are classified as LGMD2D, 2E, 2C, and 2F, respectively. METHODS: A geographical area in north east Italy (2,319,147 inhabitants) was selected for a genetic epidemiological study on primary Sarcoglycanopathies. Within the period 1982 to 1996, all patients living in this region and diagnosed with muscular dystrophy were seen at our centre. Immunohistochemical and immunoblot screening for alpha-Sarcoglycan protein deficiency was performed on all muscle biopsies from patients with a progressive muscular dystrophy of unknown aetiology and normal dystrophin. Sarcoglycan mutation analyses were conducted on all patient muscle biopsies shown to have complete or partial absence of alpha-Sarcoglycan immunostaining or a decreased quantity of alpha-Sarcoglycan protein on immunoblotting. RESULTS: Two hundred and four patient muscle biopsies were screened for alpha-Sarcoglycan protein deficiency and 18 biopsies showed a deficiency. Pathogenetic mutations involving one gene for Sarcoglycan complex components were identified in 13 patients: alpha-Sarcoglycan in seven, Beta-Sarcoglycan in two, gamma-Sarcoglycan in four, and none in the delta-Sarcoglycan gene. The overall prevalence of primary Sarcoglycanopathies, as of 31 December 1996, was estimated to be 5.6 x 10(-6) inhabitants. CONCLUSION: The prevalence rate estimated in this study is the first to be obtained after biochemical and molecular genetic screening for Sarcoglycan defects.
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β–Sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the Sarcoglycan complex
Nature genetics, 1995Co-Authors: Carsten G. Bönnemann, Mikiharu Yoshida, Satoru Noguchi, David Duggan, Corrado Angelini, Elizabeth M. Mcnally, Raju Modi, Yuji Mizuno, Emanuela Gussoni, Eric P. HoffmanAbstract:The dystrophin associated proteins (DAPs) are good candidates for harboring primary mutations in the genetically heterogeneous autosomal recessive muscular dystrophies (ARMD). The transmembrane components of the DAPs can be separated into the dystroglycan and the Sarcoglycan complexes. Here we report the isolation of cDNAs encoding the 43 kD Sarcoglycan protein Beta-Sarcoglycan (A3b) and the localization of the human gene to chromosome 4q12. We describe a young girl with ARMD with truncating mutations on both alleles. Immunostaining of her muscle biopsy shows specific loss of the components of the Sarcoglycan complex (Beta-Sarcoglycan, alpha-Sarcoglycan (adhalin), and 35 kD Sarcoglycan). Thus secondary destabilization of the Sarcoglycan complex may be an important pathophysiological event in ARMD.
Marina Mora - One of the best experts on this subject based on the ideXlab platform.
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Fibrosis and inflammation are greater in muscles of Beta-Sarcoglycan-null mouse than mdx mouse
Cell and Tissue Research, 2014Co-Authors: Sara Gibertini, Simona Zanotti, Paolo Savadori, Maurizio Curcio, Simona Saredi, Franco Salerno, Francesca Andreetta, Pia Bernasconi, Renato Mantegazza, Marina MoraAbstract:The Sgcb-null mouse, with knocked-down β-Sarcoglycan, develops severe muscular dystrophy as in type 2E human limb girdle muscular dystrophy. The mdx mouse, lacking dystrophin, is the most used model for Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little fibrosis in limb muscles. To characterize ECM protein deposition and the progression of muscle fibrosis, we evaluated protein and transcript levels of collagens I, III and VI, decorin, and TGF-β1, in quadriceps and diaphragm, at 2, 4, 8, 12, 26, and 52 weeks in Sgcb-null mice, and protein levels at 12, 26, and 52 weeks in mdx mice. In Sgcb-null mice, severe morphological disruption was present from 4 weeks in both quadriceps and diaphragm, and included conspicuous deposition of extracellular matrix components. Histopathological features of Sgcb-null mouse muscles were similar to those of age-matched mdx muscles at all ages examined, but, in the Sgcb-null mouse, the extent of connective tissue deposition was generally greater than mdx. Furthermore, in the Sgcb-null mouse, the amount of all three collagen isoforms increased steadily, while, in the mdx, they remained stable. We also found that, at 12 weeks, macrophages were significantly more numerous in mildly inflamed areas of Sgcb-null quadriceps compared to mdx quadriceps (but not in highly inflamed regions), while, in the diaphragm, macrophages did not differ significantly between the two models, in either region. Osteopontin mRNA was also significantly greater at 12 weeks in laser-dissected highly inflamed areas of the Sgcb-null quadriceps compared to the mdx quadriceps. TGF-β1 was present in areas of degeneration–regeneration, but levels were highly variable and in general did not differ significantly between the two models and controls. The roles of the various subtypes of macrophages in muscle repair and fibrosis in the two models require further study. The Sgcb-null mouse, which develops early fibrosis in limb muscles, appears more promising than the mdx mouse for probing pathogenetic mechanisms of muscle fibrosis and for developing anti-fibrotic treatments. Highlights • The Sgcb-null mouse develops severe muscular dystrophy, the mdx mouse does not. • Fibrosis developed earlier in Sgcb-null quadriceps and diaphragm than mdx . • Macrophages were commoner in mildly inflamed parts of Sgcb-null quadriceps than mdx . • The Sgcb-null model appears more useful than mdx for studying fibrotic mechanisms. • The Sgcb-null model also appears more useful for developing anti-fibrotic treatments.
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Fibrosis and inflammation are greater in muscles of Beta-Sarcoglycan-null mouse than mdx mouse
Cell and tissue research, 2014Co-Authors: Sara Gibertini, Simona Zanotti, Paolo Savadori, Maurizio Curcio, Simona Saredi, Franco Salerno, Francesca Andreetta, Pia Bernasconi, Renato Mantegazza, Marina MoraAbstract:The Sgcb-null mouse, with knocked-down β-Sarcoglycan, develops severe muscular dystrophy as in type 2E human limb girdle muscular dystrophy. The mdx mouse, lacking dystrophin, is the most used model for Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little fibrosis in limb muscles. To characterize ECM protein deposition and the progression of muscle fibrosis, we evaluated protein and transcript levels of collagens I, III and VI, decorin, and TGF-β1, in quadriceps and diaphragm, at 2, 4, 8, 12, 26, and 52 weeks in Sgcb-null mice, and protein levels at 12, 26, and 52 weeks in mdx mice. In Sgcb-null mice, severe morphological disruption was present from 4 weeks in both quadriceps and diaphragm, and included conspicuous deposition of extracellular matrix components. Histopathological features of Sgcb-null mouse muscles were similar to those of age-matched mdx muscles at all ages examined, but, in the Sgcb-null mouse, the extent of connective tissue deposition was generally greater than mdx. Furthermore, in the Sgcb-null mouse, the amount of all three collagen isoforms increased steadily, while, in the mdx, they remained stable. We also found that, at 12 weeks, macrophages were significantly more numerous in mildly inflamed areas of Sgcb-null quadriceps compared to mdx quadriceps (but not in highly inflamed regions), while, in the diaphragm, macrophages did not differ significantly between the two models, in either region. Osteopontin mRNA was also significantly greater at 12 weeks in laser-dissected highly inflamed areas of the Sgcb-null quadriceps compared to the mdx quadriceps. TGF-β1 was present in areas of degeneration–regeneration, but levels were highly variable and in general did not differ significantly between the two models and controls. The roles of the various subtypes of macrophages in muscle repair and fibrosis in the two models require further study. The Sgcb-null mouse, which develops early fibrosis in limb muscles, appears more promising than the mdx mouse for probing pathogenetic mechanisms of muscle fibrosis and for developing anti-fibrotic treatments.
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P.20.9 Muscle fibrosis in the sgcb-null mouse model versus the mdx model
Neuromuscular Disorders, 2013Co-Authors: Sara Gibertini, Simona Zanotti, Paolo Savadori, Maurizio Curcio, Marina MoraAbstract:The Sgcb-null mouse model, with Beta-Sarcoglycan knocked-down, develops severe muscular dystrophy with early fibrosis like the human limb girdle muscular dystrophy type 2E. The mdx mouse, lacking dystrophin, is the most used model for Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little endomysial fibrosis in limb muscles. We have characterized the progression of muscle fibrosis, at molecular and histopathological level, in the Sgcb-null mouse and compared results to findings in the mdx. We evaluated expression of collagen I, III and VI, and of decorin and TGFBeta1 by immunohistochemistry or immunoblotting, and transcript levels by Real-Time PCR, in the quadriceps and diaphragm muscles, at 2, 4, 8, 12, 26 and 52 weeks in the sgcb-null mouse, and at 12, 26 and 52 weeks in the mdx. We found severe histopathological features from 4 weeks on, and concomitant deposition of extracellular matrix components in the Sgcb-null mouse, with collagen I, III and VI significantly increased since early ages both in the quadriceps and diaphragm. When compared to the mdx muscles, histopatological features of both Sgcb-null and age-matched mdx mice were similar at all examined ages except that in Sgcb-null mice the extent of connective tissue was generally greater. This was particularly evident in the quadriceps muscle where the endomysial connective tissue was prominent and the extent of the various collagens was significantly greater in the Sgcb-null mice at all ages compared to mdx. Furthermore, differently than in the Scgb-null mouse, where the amount all of three collagen isoforms increased steadily, in the mdx they remained stable. The Sgcb-null mouse represents a useful model for evaluating the pathogenetic mechanisms of muscle fibrosis and for development of anti-fibrotic treatments.
Eric Villard - One of the best experts on this subject based on the ideXlab platform.
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Mutational analysis of the Beta- and delta-Sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy.
American journal of medical genetics. Part A, 2003Co-Authors: Nicolas Sylvius, Laetitia Duboscq-bidot, Christiane Bouchier, Philippe Charron, Abdelaziz Benaiche, Pascale Sébillon, Michel Komajda, Eric VillardAbstract:Dilated cardiomyopathy (DCM) is defined by ventricular dilatation associated with impaired contractile function. Approximately one-third of idiopathic dilated cardiomyopathy cases are due to inherited gene mutations. Mutations in the Beta- and delta-Sarcoglycan genes have been described in limb girdle muscular dystrophy and/or isolated DCM. In this study, the aim was to investigate the prevalence of these genes in isolated DCM. We screened these two genes for mutations in 99 unrelated patients with sporadic or familial DCM. The coding exon and intron-exon boundaries of each gene were amplified by polymerase chain reaction. Mutation analyses were performed by single-strand conformation polymorphism for the Beta-Sarcoglycan gene and by direct sequencing for the delta-Sarcoglycan gene. New polymorphisms, as well as already described ones, were found in these two genes, but none appeared to be responsible for dilated cardiomyopathy. We, therefore, conclude that these genes are not responsible for idiopathic isolated dilated cardiomyopathy in our population. Furthermore, based on previously published and present data, we could estimate the prevalence of delta-Sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease.
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Mutational analysis of the β- and δ-Sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy
American Journal of Medical Genetics Part A, 2003Co-Authors: Nicolas Sylvius, Laetitia Duboscq-bidot, Christiane Bouchier, Philippe Charron, Abdelaziz Benaiche, Pascale Sébillon, Michel Komajda, Eric VillardAbstract:Dilated cardiomyopathy (DCM) is defined by ventricular dilatation associated with impaired contractile function. Approximately one-third of idiopathic dilated cardiomyopathy cases are due to inherited gene mutations. Mutations in the Beta- and delta-Sarcoglycan genes have been described in limb girdle muscular dystrophy and/or isolated DCM. In this study, the aim was to investigate the prevalence of these genes in isolated DCM. We screened these two genes for mutations in 99 unrelated patients with sporadic or familial DCM. The coding exon and intron-exon boundaries of each gene were amplified by polymerase chain reaction. Mutation analyses were performed by single-strand conformation polymorphism for the Beta-Sarcoglycan gene and by direct sequencing for the delta-Sarcoglycan gene. New polymorphisms, as well as already described ones, were found in these two genes, but none appeared to be responsible for dilated cardiomyopathy. We, therefore, conclude that these genes are not responsible for idiopathic isolated dilated cardiomyopathy in our population. Furthermore, based on previously published and present data, we could estimate the prevalence of delta-Sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease.
Sara Gibertini - One of the best experts on this subject based on the ideXlab platform.
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Fibrosis and inflammation are greater in muscles of Beta-Sarcoglycan-null mouse than mdx mouse
Cell and Tissue Research, 2014Co-Authors: Sara Gibertini, Simona Zanotti, Paolo Savadori, Maurizio Curcio, Simona Saredi, Franco Salerno, Francesca Andreetta, Pia Bernasconi, Renato Mantegazza, Marina MoraAbstract:The Sgcb-null mouse, with knocked-down β-Sarcoglycan, develops severe muscular dystrophy as in type 2E human limb girdle muscular dystrophy. The mdx mouse, lacking dystrophin, is the most used model for Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little fibrosis in limb muscles. To characterize ECM protein deposition and the progression of muscle fibrosis, we evaluated protein and transcript levels of collagens I, III and VI, decorin, and TGF-β1, in quadriceps and diaphragm, at 2, 4, 8, 12, 26, and 52 weeks in Sgcb-null mice, and protein levels at 12, 26, and 52 weeks in mdx mice. In Sgcb-null mice, severe morphological disruption was present from 4 weeks in both quadriceps and diaphragm, and included conspicuous deposition of extracellular matrix components. Histopathological features of Sgcb-null mouse muscles were similar to those of age-matched mdx muscles at all ages examined, but, in the Sgcb-null mouse, the extent of connective tissue deposition was generally greater than mdx. Furthermore, in the Sgcb-null mouse, the amount of all three collagen isoforms increased steadily, while, in the mdx, they remained stable. We also found that, at 12 weeks, macrophages were significantly more numerous in mildly inflamed areas of Sgcb-null quadriceps compared to mdx quadriceps (but not in highly inflamed regions), while, in the diaphragm, macrophages did not differ significantly between the two models, in either region. Osteopontin mRNA was also significantly greater at 12 weeks in laser-dissected highly inflamed areas of the Sgcb-null quadriceps compared to the mdx quadriceps. TGF-β1 was present in areas of degeneration–regeneration, but levels were highly variable and in general did not differ significantly between the two models and controls. The roles of the various subtypes of macrophages in muscle repair and fibrosis in the two models require further study. The Sgcb-null mouse, which develops early fibrosis in limb muscles, appears more promising than the mdx mouse for probing pathogenetic mechanisms of muscle fibrosis and for developing anti-fibrotic treatments. Highlights • The Sgcb-null mouse develops severe muscular dystrophy, the mdx mouse does not. • Fibrosis developed earlier in Sgcb-null quadriceps and diaphragm than mdx . • Macrophages were commoner in mildly inflamed parts of Sgcb-null quadriceps than mdx . • The Sgcb-null model appears more useful than mdx for studying fibrotic mechanisms. • The Sgcb-null model also appears more useful for developing anti-fibrotic treatments.
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Fibrosis and inflammation are greater in muscles of Beta-Sarcoglycan-null mouse than mdx mouse
Cell and tissue research, 2014Co-Authors: Sara Gibertini, Simona Zanotti, Paolo Savadori, Maurizio Curcio, Simona Saredi, Franco Salerno, Francesca Andreetta, Pia Bernasconi, Renato Mantegazza, Marina MoraAbstract:The Sgcb-null mouse, with knocked-down β-Sarcoglycan, develops severe muscular dystrophy as in type 2E human limb girdle muscular dystrophy. The mdx mouse, lacking dystrophin, is the most used model for Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little fibrosis in limb muscles. To characterize ECM protein deposition and the progression of muscle fibrosis, we evaluated protein and transcript levels of collagens I, III and VI, decorin, and TGF-β1, in quadriceps and diaphragm, at 2, 4, 8, 12, 26, and 52 weeks in Sgcb-null mice, and protein levels at 12, 26, and 52 weeks in mdx mice. In Sgcb-null mice, severe morphological disruption was present from 4 weeks in both quadriceps and diaphragm, and included conspicuous deposition of extracellular matrix components. Histopathological features of Sgcb-null mouse muscles were similar to those of age-matched mdx muscles at all ages examined, but, in the Sgcb-null mouse, the extent of connective tissue deposition was generally greater than mdx. Furthermore, in the Sgcb-null mouse, the amount of all three collagen isoforms increased steadily, while, in the mdx, they remained stable. We also found that, at 12 weeks, macrophages were significantly more numerous in mildly inflamed areas of Sgcb-null quadriceps compared to mdx quadriceps (but not in highly inflamed regions), while, in the diaphragm, macrophages did not differ significantly between the two models, in either region. Osteopontin mRNA was also significantly greater at 12 weeks in laser-dissected highly inflamed areas of the Sgcb-null quadriceps compared to the mdx quadriceps. TGF-β1 was present in areas of degeneration–regeneration, but levels were highly variable and in general did not differ significantly between the two models and controls. The roles of the various subtypes of macrophages in muscle repair and fibrosis in the two models require further study. The Sgcb-null mouse, which develops early fibrosis in limb muscles, appears more promising than the mdx mouse for probing pathogenetic mechanisms of muscle fibrosis and for developing anti-fibrotic treatments.
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P.20.9 Muscle fibrosis in the sgcb-null mouse model versus the mdx model
Neuromuscular Disorders, 2013Co-Authors: Sara Gibertini, Simona Zanotti, Paolo Savadori, Maurizio Curcio, Marina MoraAbstract:The Sgcb-null mouse model, with Beta-Sarcoglycan knocked-down, develops severe muscular dystrophy with early fibrosis like the human limb girdle muscular dystrophy type 2E. The mdx mouse, lacking dystrophin, is the most used model for Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little endomysial fibrosis in limb muscles. We have characterized the progression of muscle fibrosis, at molecular and histopathological level, in the Sgcb-null mouse and compared results to findings in the mdx. We evaluated expression of collagen I, III and VI, and of decorin and TGFBeta1 by immunohistochemistry or immunoblotting, and transcript levels by Real-Time PCR, in the quadriceps and diaphragm muscles, at 2, 4, 8, 12, 26 and 52 weeks in the sgcb-null mouse, and at 12, 26 and 52 weeks in the mdx. We found severe histopathological features from 4 weeks on, and concomitant deposition of extracellular matrix components in the Sgcb-null mouse, with collagen I, III and VI significantly increased since early ages both in the quadriceps and diaphragm. When compared to the mdx muscles, histopatological features of both Sgcb-null and age-matched mdx mice were similar at all examined ages except that in Sgcb-null mice the extent of connective tissue was generally greater. This was particularly evident in the quadriceps muscle where the endomysial connective tissue was prominent and the extent of the various collagens was significantly greater in the Sgcb-null mice at all ages compared to mdx. Furthermore, differently than in the Scgb-null mouse, where the amount all of three collagen isoforms increased steadily, in the mdx they remained stable. The Sgcb-null mouse represents a useful model for evaluating the pathogenetic mechanisms of muscle fibrosis and for development of anti-fibrotic treatments.
Nicolas Sylvius - One of the best experts on this subject based on the ideXlab platform.
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Mutational analysis of the Beta- and delta-Sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy.
American journal of medical genetics. Part A, 2003Co-Authors: Nicolas Sylvius, Laetitia Duboscq-bidot, Christiane Bouchier, Philippe Charron, Abdelaziz Benaiche, Pascale Sébillon, Michel Komajda, Eric VillardAbstract:Dilated cardiomyopathy (DCM) is defined by ventricular dilatation associated with impaired contractile function. Approximately one-third of idiopathic dilated cardiomyopathy cases are due to inherited gene mutations. Mutations in the Beta- and delta-Sarcoglycan genes have been described in limb girdle muscular dystrophy and/or isolated DCM. In this study, the aim was to investigate the prevalence of these genes in isolated DCM. We screened these two genes for mutations in 99 unrelated patients with sporadic or familial DCM. The coding exon and intron-exon boundaries of each gene were amplified by polymerase chain reaction. Mutation analyses were performed by single-strand conformation polymorphism for the Beta-Sarcoglycan gene and by direct sequencing for the delta-Sarcoglycan gene. New polymorphisms, as well as already described ones, were found in these two genes, but none appeared to be responsible for dilated cardiomyopathy. We, therefore, conclude that these genes are not responsible for idiopathic isolated dilated cardiomyopathy in our population. Furthermore, based on previously published and present data, we could estimate the prevalence of delta-Sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease.
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Mutational analysis of the β- and δ-Sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy
American Journal of Medical Genetics Part A, 2003Co-Authors: Nicolas Sylvius, Laetitia Duboscq-bidot, Christiane Bouchier, Philippe Charron, Abdelaziz Benaiche, Pascale Sébillon, Michel Komajda, Eric VillardAbstract:Dilated cardiomyopathy (DCM) is defined by ventricular dilatation associated with impaired contractile function. Approximately one-third of idiopathic dilated cardiomyopathy cases are due to inherited gene mutations. Mutations in the Beta- and delta-Sarcoglycan genes have been described in limb girdle muscular dystrophy and/or isolated DCM. In this study, the aim was to investigate the prevalence of these genes in isolated DCM. We screened these two genes for mutations in 99 unrelated patients with sporadic or familial DCM. The coding exon and intron-exon boundaries of each gene were amplified by polymerase chain reaction. Mutation analyses were performed by single-strand conformation polymorphism for the Beta-Sarcoglycan gene and by direct sequencing for the delta-Sarcoglycan gene. New polymorphisms, as well as already described ones, were found in these two genes, but none appeared to be responsible for dilated cardiomyopathy. We, therefore, conclude that these genes are not responsible for idiopathic isolated dilated cardiomyopathy in our population. Furthermore, based on previously published and present data, we could estimate the prevalence of delta-Sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease.