The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Elizabeth M. Mcnally - One of the best experts on this subject based on the ideXlab platform.
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M.I.2 The matrix as a modifier for muscular dystrophy
Neuromuscular Disorders, 2013Co-Authors: Elizabeth M. McnallyAbstract:Duchenne muscular dystrophy and the limb girdle muscular dystrophies, like other Mendelian disorders, are modified by genetic and environmental factors. We set out to identify modifiers of muscular dystrophy using a mouse model of LGMD 2C. Mice deleted for Gamma Sarcoglycan (Sgcg), a dystrophin associated protein, were used for mapping genetic modifiers because humans with LGMD 2C often display a variable phenotype despite having the same identical mutation. We used an intercross between Sgcg mice in the DBA2J background, which confers a severe phenotype, and Sgcg mice in the 129T2/SvEmsJ, which confers a mild background. A genomewide scan identified a locus on murine chromosome 7 that modified two different aspects of muscular dystrophy pathology. The chromosome 7 locus regulated fibrosis and also Evans blue dye uptake into skeletal muscle, a marker of sarcolemmal leakage. An insertion/deletion polymorphism was identified in the Ltbp4 gene, and this polymorphism correlated with severity of muscular dystrophy. In collaboration with the United Dystrophinopathy project, we queried whether human LTBP4 genotype correlated with outcome in DMD patients. We identified that LTBP4 acted as a modifier of DMD. LTBP4 is the latent TGFbeta binding protein and a member of the fibrillin superfamily. The members of this family reside within the extracellular matrix where they participate in binding and sequestering TGFbeta proteins. Release of TGFbeta proteins from the matrix permits ligand binding to cell surface TGFbeta receptors and activation of intracellular TGFbeta signaling. Together, these data, from mouse models and human patients, support that hyper-TGFbeta signaling is pathogenic in DMD and LGMDs, and suggest that reduction of TGFbeta signaling may be therapeutic.
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A novel FKRP mutation in congenital muscular dystrophy disrupts the dystrophin glycoprotein complex.
Neuromuscular disorders : NMD, 2007Co-Authors: Heather Macleod, Peter Pytel, Robert L. Wollmann, Ewa Chelmicka-schorr, Kenneth Silver, Rebecca Anderson, Darrel Waggoner, Elizabeth M. McnallyAbstract:Mutations in the gene encoding fukutin related protein (FKRP) produce a spectrum of disease including congenital muscular dystrophy and limb girdle muscular dystrophy. FKRP is one member of a class of molecules thought to be glycosyltransferases that mediate O-linked glycosylation. The primary target of these glycosyltransferases is thought to be dystroglycan. We now report two unrelated Mexican children with congenital muscular dystrophy who each have the identical, novel 1387A>G, N463D mutation. Muscle biopsies from these children show a reduction of alpha-dystroglycan and also show reduction of beta-dystroglycan, and alpha-, beta-, and Gamma-Sarcoglycan, suggesting that FKRP mutations can perturb membrane associated proteins beyond dystroglycan.
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Genetic background influences muscular dystrophy.
Neuromuscular disorders : NMD, 2005Co-Authors: Ahlke Heydemann, Michele Hadhazy, Jill M. Huber, Alexis Demonbreun, Elizabeth M. McnallyAbstract:Mutations in the genes encoding dystrophin and its associated proteins, the Sarcoglycans, lead to muscular dystrophy in humans and in mouse models. In the presence of identical gene mutations, the muscular dystrophy phenotype can be highly variable. Using a mouse model of limb girdle muscular dystrophy engineered with a null allele of Gamma-Sarcoglycan, we bred the identical Gamma-Sarcoglycan mutation into four different genetic backgrounds. We found that the Gamma-Sarcoglycan mutation is least severe in the129SV/J (129) strain and most severe on the DBA 2J JAX (DBA) strain using quantitative measures of Evan's blue dye uptake, as a marker of membrane permeability defects, and hydroxyproline content, as a marker of fibrosis. In addition we show that the DBA mice are most severely affected regardless of gender and age. The enhanced phenotype observed in the DBA strain was not caused by exercise as the DBA mice scored the lowest in a voluntary activity test. The milder phenotype seen in the 129SV/J and C57B6/J strains suggests that these backgrounds contain modifier loci that partially suppress the muscular dystrophy phenotype. Identification of these modifier genes and the associated pathways may lead to novel therapeutic strategies.
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Genetic compensation for Sarcoglycan loss by integrin alpha7beta1 in muscle.
Journal of cell science, 2004Co-Authors: Michael J Allikian, Andrew A. Hack, Stephanie Mewborn, Ulrike Mayer, Elizabeth M. McnallyAbstract:Disruption of the Sarcoglycan complex leads to muscle membrane instability and muscular dystrophy in humans and mice. Through the dystrophin glycoprotein complex, Sarcoglycan participates in connecting the internal cytoskeleton to the membrane and the extracellular matrix. Integrin alpha7beta1 is also a transmembrane protein of skeletal and cardiac muscle that similarly links the cytoskeleton to the extracellular matrix. Mice lacking integrin alpha7 develop mild muscle degeneration, while Sarcoglycan mutant mice display overt muscle degeneration and muscular dystrophy. In Sarcoglycan-deficient muscle, integrin alpha7 protein was upregulated at the plasma membrane. To ascertain whether integrin alpha7 upregulation compensates for the loss of the transmembrane Sarcoglycan linkage in Sarcoglycan-deficient muscle, we generated mice lacking both integrin alpha7 and Gamma-Sarcoglycan (gxi). These double-mutant gxi mice exhibit profound, rapid muscle degeneration leading to death before one month of age consistent with a weakened cellular attachment to the extracellular matrix. The regenerative capacity of gxi muscle was intact with increased embryonic myosin heavy chain expression, myofiber central nucleation and normal in vivo myoblast differentiation. Therefore, upregulation of integrin alpha7beta1 compensates as a transmembrane muscle cell attachment for Sarcoglycan consistent with overlapping roles for Sarcoglycan and integrins in mediating cytoskeletal-membrane-extracellular matrix interaction.
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Functional nitric oxide synthase mislocalization in cardiomyopathy.
Journal of molecular and cellular cardiology, 2004Co-Authors: Ahlke Heydemann, Jill M. Huber, Rahul Kakkar, Matthew T. Wheeler, Elizabeth M. McnallyAbstract:Mutations in the dystrophin glycoprotein complex, and in particular the Sarcoglycan subcomplex, lead to cardiomyopathy and muscular dystrophy. Mice with mutations in Gamma-Sarcoglycan or delta-Sarcoglycan develop cardiomyopathy that is characterized by focal regions of tissue damage. These focally damaged regions constitute 0-5% of cardiac tissue. In cardiomyopathy arising from Sarcoglycan mutations, we found that endothelial nitric oxide synthase (eNOS) was significantly increased in focally damaged cardiac myocytes. In addition, we noted that nitric oxide (NO) was also increased in regions of tissue damage and altered membrane permeability. In Sarcoglycan mutant mice, regionally increased cardiac NO was associated with hypersensitivity to carbachol and decreased sensitivity to adrenergic stimulation. Inhibition of NO production in Sarcoglycan mutant mice was associated with improved recovery after carbachol and isoproterenol infusion. These data provide a mechanism where regional, focal cardiac damage creates pathologic gradients of NO. Moreover, inhibition of nitric oxide synthase corrects defects that arise from pathologic NO gradients.
Michel Fardeau - One of the best experts on this subject based on the ideXlab platform.
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molecular and genetic characterization of sarcospan insights into Sarcoglycan sarcospan interactions
Human Molecular Genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
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Molecular and genetic characterization of sarcospan: insights into Sarcoglycan–sarcospan interactions
Human molecular genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
Steven A. Moore - One of the best experts on this subject based on the ideXlab platform.
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Expression of γ-Sarcoglycan in Smooth Muscle and Its Interaction with the Smooth Muscle Sarcoglycan-Sarcospan Complex
The Journal of biological chemistry, 2000Co-Authors: Rita Barresi, Steven A. Moore, Catherine A. Stolle, Jerry R. MendellAbstract:The Sarcoglycan complex in striated muscle is a heterotetrameric unit integrally associated with sarcospan in the dystrophin-glycoprotein complex. The Sarcoglycans, alpha, beta, Gamma, and delta, are mutually dependent with regard to their localization at the sarcolemma, and mutations in any of the Sarcoglycan genes lead to limb-girdle muscular dystrophies type 2C-2F. In smooth muscle beta- and delta-Sarcoglycans are associated with epsilon-Sarcoglycan, a glycoprotein homologous to alpha-Sarcoglycan. Here, we demonstrate that Gamma-Sarcoglycan is also a component of the Sarcoglycan complex in the smooth muscle. First, we show the presence of Gamma-Sarcoglycan in a number of smooth muscle-containing organs, and we verify the existence of identical transcripts in skeletal and smooth muscle. The specificity of the expression of Gamma-Sarcoglycan in smooth muscle was confirmed by analysis of smooth muscle cells in culture. Next, we provide evidence for the association of Gamma-Sarcoglycan with the Sarcoglycan-sarcospan complex by biochemical analysis and comparison among animal models for muscular dystrophy. Moreover, we find disruption of the Sarcoglycan complex in the vascular smooth muscle of a patient with Gamma-Sarcoglycanopathy. Taken together, our results prove that the Sarcoglycan complex in vascular and visceral smooth muscle consists of epsilon-, beta-, Gamma-, and delta-Sarcoglycans and is associated with sarcospan.
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molecular and genetic characterization of sarcospan insights into Sarcoglycan sarcospan interactions
Human Molecular Genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
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Molecular and genetic characterization of sarcospan: insights into Sarcoglycan–sarcospan interactions
Human molecular genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
Catherine A. Stolle - One of the best experts on this subject based on the ideXlab platform.
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Expression of γ-Sarcoglycan in Smooth Muscle and Its Interaction with the Smooth Muscle Sarcoglycan-Sarcospan Complex
The Journal of biological chemistry, 2000Co-Authors: Rita Barresi, Steven A. Moore, Catherine A. Stolle, Jerry R. MendellAbstract:The Sarcoglycan complex in striated muscle is a heterotetrameric unit integrally associated with sarcospan in the dystrophin-glycoprotein complex. The Sarcoglycans, alpha, beta, Gamma, and delta, are mutually dependent with regard to their localization at the sarcolemma, and mutations in any of the Sarcoglycan genes lead to limb-girdle muscular dystrophies type 2C-2F. In smooth muscle beta- and delta-Sarcoglycans are associated with epsilon-Sarcoglycan, a glycoprotein homologous to alpha-Sarcoglycan. Here, we demonstrate that Gamma-Sarcoglycan is also a component of the Sarcoglycan complex in the smooth muscle. First, we show the presence of Gamma-Sarcoglycan in a number of smooth muscle-containing organs, and we verify the existence of identical transcripts in skeletal and smooth muscle. The specificity of the expression of Gamma-Sarcoglycan in smooth muscle was confirmed by analysis of smooth muscle cells in culture. Next, we provide evidence for the association of Gamma-Sarcoglycan with the Sarcoglycan-sarcospan complex by biochemical analysis and comparison among animal models for muscular dystrophy. Moreover, we find disruption of the Sarcoglycan complex in the vascular smooth muscle of a patient with Gamma-Sarcoglycanopathy. Taken together, our results prove that the Sarcoglycan complex in vascular and visceral smooth muscle consists of epsilon-, beta-, Gamma-, and delta-Sarcoglycans and is associated with sarcospan.
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molecular and genetic characterization of sarcospan insights into Sarcoglycan sarcospan interactions
Human Molecular Genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
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Molecular and genetic characterization of sarcospan: insights into Sarcoglycan–sarcospan interactions
Human molecular genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
Rachelle H. Crosbie - One of the best experts on this subject based on the ideXlab platform.
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molecular and genetic characterization of sarcospan insights into Sarcoglycan sarcospan interactions
Human Molecular Genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
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Molecular and genetic characterization of sarcospan: insights into Sarcoglycan–sarcospan interactions
Human molecular genetics, 2000Co-Authors: Rachelle H. Crosbie, Steven A. Moore, Catherine A. Stolle, Leland E Lim, Michio Hirano, Arthur P Hays, Simon W Maybaum, H Collin, Sherri A Dovico, Michel FardeauAbstract:Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the Sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the Sarcoglycans. In particular, sarcospan was absent in a Gamma-Sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-Sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric Sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the Sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the Gamma-Sarcoglycan gene, which causes premature truncation of Gamma-Sarcoglycan without affecting assembly of the mutant Gamma-Sarcoglycan into a complex with alpha-, beta- and delta-Sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant Sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of Gamma-Sarcoglycan is critical for the functioning of the entire Sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper Sarcoglycan-sarcospan expression and function.
