Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sarcospan is an integral membrane component of the dystrophin-glycoprotein complex (DGC) found at the sarcolemma of striated and smooth muscle. The DGC plays important roles in muscle function and viability as evidenced by defects in components of the DGC, which cause muscular dystrophy. Sarcospan is unique among the components of the complex in that it contains four transmembrane domains with intracellular N- and C-terminal domains and is a member of the tetraspan superfamily of proteins. Sarcospan is tightly linked to the sarcoglycans, and together these proteins form a subcomplex within the DGC. Stable expression of sarcospan at the sarcolemma is dependent upon expression of the sarcoglycans. Here we describe the generation and analysis of mice carrying a null mutation in the Sspn gene. Surprisingly, the Sspn-deficient muscle maintains expression of other components of the DGC at the sarcolemma, and no gross histological abnormalities of muscle from the mice are observed. The Sspn-deficient muscle maintains sarcolemmal integrity as determined by serum creatine kinase and Evans blue uptake assays, and the Sspn-deficient muscle maintains normal force and power generation capabilities. These data suggest either that sarcospan is not required for normal DGC function or that the Sspn-deficient muscle is compensating for the absence of sarcospan, perhaps by utilizing another protein to carry out its function.
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PMID:Sarcospan-deficient mice maintain normal muscle function. 1066 44

Muscular dystrophy is a heterogeneous genetic disease that affects skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in dystrophin and its associated glycoproteins, the sarcoglycans. Furthermore, defects in dystrophin have been shown to cause a disruption of the normal expression and localization of the sarcoglycan complex. Thus, abnormalities of sarcoglycan are a common molecular feature in a number of dystrophies. By combining biochemistry, molecular cell biology, and human and mouse genetics, a growing understanding of the sarcoglycan complex is emerging. Sarcoglycan appears to be an important, independent mediator of dystrophic pathology in both skeletal muscle and heart. The absence of sarcoglycan leads to alterations of membrane permeability and apoptosis, two shared features of a number of dystrophies. beta-sarcoglycan and delta-sarcoglycan may form the core of the sarcoglycan subcomplex with alpha- and gamma-sarcoglycan less tightly associated to this core. The relationship of epsilon-sarcoglycan to the dystrophin-glycoprotein complex remains unclear. Animals lacking alpha-, gamma- and delta-sarcoglycan have been described and provide excellent opportunities for further investigation of the function of sarcoglycan. Dystrophin with dystroglycan and laminin may be a mechanical link between the actin cytoskeleton and the extracellular matrix. By positioning itself in close proximity to dystrophin and dystroglycan, sarcoglycan may function to couple mechanical and chemical signals in striated muscle. Sarcoglycan may be an independent signaling or regulatory module whose position in the membrane is determined by dystrophin but whose function is carried out independent of the dystrophin-dystroglycan-laminin axis.
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PMID:Sarcoglycans in muscular dystrophy. 1067 64

The laminina2-chain gene (LAMA2) encodes a basal lamina protein, laminina2, known to be deficient in one form of congenital muscular dystrophy (CMD). In a laminina2 deficient-CMD patient, we screened the entire LAMA2 cDNA (953bp) by reverse transcriptase polymerase chain reaction combined with single strand conformational polymorphism analysis. Direct sequencing of aberrant conformers in this patient revealed two loss-of-function mutations, consistent with autosomal recessive inheritance. The patient had two novel heterozygous mutations: 1) an exon 4 nonsense mutation caused by a G-->A substitution at cDNA position 547, changing the TGG codon for tryptophan into a TGA stop codon (W166X) in the N-terminus domain VI;ii) an exon 54 frameshift mutation due to a deletion of nucleotide 'C' at cDNA position 7707 (S2553Y), resulting in a premature stop codon (V2587X) in exon 55 in the globular G domain of laminina2 at the C-terminus. These mutations cause a disruption of the open reading frame of LAMA2. The absence of laminina2 observed in the patient's muscle biopsy could result from diminished levels of the LAMA2 transcript. Alternatively, the mutations might lead to translation of a truncated laminina2. By either mechanism the phenotype of congenital muscular dystrophy is believed to be the result of disruption of linkage between the extracellular matrix and the dystrophin glycoprotein complex.
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PMID:Novel compound heterozygous laminina2-chain gene (LAMA2) mutations in congenital muscular dystrophy. Mutations in brief no. 159. Online. 1069 16

New discoveries have dramatically changed the way we approach and think about patients with childhood muscular dystrophies. An aura of order and organization seems to be at hand for a group of diseases which previously seemed endlessly heterogeneous. We have learned that young boys and girls with proximal muscle weakness, large calves and elevated serum CK may have any one of a number of closely connected disorders which affect a complex of interacting proteins of the dystrophin-glycoprotein complex. This complex links the intracellular cytoskeleton to the extracellular matrix. Patients with Duchenne and Becker dystrophies lack dystrophin, while some of the limb girdle muscular dystrophies (an archaic term) are deficient in sarcoglycans and other proteins. The concept of interrelated disorders extends to the previously orphaned distal muscular dystrophies, or distal myopathies, as they are often called. A surprise finding is that the C. elegans protein, dysferlin, is conserved and expressed in man. We know little of the function of this protein in human primates, but its loss in muscle has brought seemingly disparate disorders together, since both a form of LGMD (2B) and distal myopathy (Miyoshi myopathy) are deficient in this same gene product. The congenital muscular dystrophies are also well-entrenched in our expanding concepts of orderliness of disease. The defect in the laminin-alpha2 chain, a direct ligand to the dystrophin-glycoprotein complex, causes a form of muscular dystrophy which affects infants. Another variant of congenital muscular dystrophy is deficient the integrin alpha7, an important laminin receptor. Finally, in Fukuyama congenital muscular dystrophy, the deficient fukutin gene product may also be linked to the basal lamina, permitting overmigration of neuronal cells which lead to micropolygyria in the brain, and at the same time cause basal lamina defects in the extracellular matrix of skeletal muscle, which leads to muscular dystrophy. As we approach the millennium, those of us who have seen the transition from the pre-molecular to the molecular era of myology know that we leave behind a great legacy of chaos (no great loss), replaced by a foundation for conceptual organization which will serve to establish new roots for research as well as for the enriched practice of medicine. The future looks bright for our field and our patients!
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PMID:The childhood muscular dystrophies: making order out of chaos. 1071 85

Two membrane proteins express the antigens that comprise the Kell blood group system. A single antigen, Kx, is carried on XK, a 440-amino acid protein that spans the membrane 10 times, and more than 20 antigens reside on Kell, a 93-kd, type II glycoprotein. XK and Kell are linked, close to the membrane surface, by a single disulfide bond between Kell cysteine 72 and XK cysteine 347. Although primarily expressed in erythroid tissues, Kell and XK are also present in many other tissues. The polymorphic forms of Kell are due to single base mutations that encode different amino acids. Some Kell antigens are highly immunogenic and may cause strong reactions if mismatched blood is transfused and severe fetal anemia in sensitized mothers. Antibodies to KEL1 may suppress erythropoiesis at the progenitor level, leading to fetal anemia. The cellular functions of Kell/XK are complex. Absence of XK, the McLeod phenotype, is associated with acanthocytic red blood cells (RBCs), and with late-onset forms of muscular dystrophy and nerve abnormalities. Kell, by homology, is a member of the neprilysin (M13) family of membrane zinc endopeptidases and it preferentially activates endothelin-3 by specific cleavage of the Trp21-Ile22 bond of big endothelin-3.
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PMID:The Kell blood group system: Kell and XK membrane proteins. 1079 80

Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking (delta)-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking (gamma)-sarcoglycan. However, unlike muscle lacking (gamma)-sarcoglycan, (delta)-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of (delta)-sarcoglycan, (alpha)-, (beta)- and (gamma)-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without (gamma)-sarcoglycan, reduced levels of (alpha)-, (beta)- and (delta)-sarcoglycan were expressed, glycosylated and formed a complex with each other. Thus, the elimination of (gamma)- and (delta)-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences were associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.
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PMID:Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex. 1086 11

In humans, a subset of cases of Limb-girdle muscular dystrophy (LGMD) arise from mutations in the genes encoding one of the sarcoglycan (alpha, beta, gamma, or delta) subunits of the dystrophin-glycoprotein complex. While adeno-associated virus (AAV) is a potential gene therapy vector for these dystrophies, it is unclear if AAV can be used if a diseased muscle is undergoing rapid degeneration and necrosis. The skeletal muscles of mice lacking gamma-sarcoglycan (gsg-/- mice) differ from the animal models that have been evaluated to date in that the severity of the skeletal muscle pathology is much greater and more representative of that of humans with muscular dystrophy. Following direct muscle injection of a recombinant AAV [in which human gamma-sarcoglycan expression is driven by a truncated muscle creatine kinase (MCK) promoter/enhancer], we observed significant numbers of muscle fibers expressing gamma-sarcoglycan and an overall improvement of the histologic pattern of dystrophy. However, these results could be achieved only if injections into the muscle were prior to the development of significant fibrosis in the muscle. The results presented in this report show promise for AAV gene therapy for LGMD, but underscore the need for intervention early in the time course of the disease process.
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PMID:Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer. 1093 22

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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PMID:Expression of gamma -sarcoglycan in smooth muscle and its interaction with the smooth muscle sarcoglycan-sarcospan complex. 1099 4

Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the pathogenesis of autosomal dominant limb girdle muscular dystrophy 1C. Here we report on a 4-year-old girl presenting with myalgia and muscle cramps due to a caveolin-3 deficiency in her dystrophic skeletal muscle as a result of a heterozygous 136G-->A substitution in the caveolin-3 gene. The novel sporadic missense mutation in the caveolin signature sequence of the caveolin-3 gene changes an alanine to a threonine (A46T) and prevents the localization of caveolin-3 to the plasma membrane in a dominant negative fashion. Caveolin-3 has been suggested to interact with the dystrophin-glycoprotein complex, which in striated muscle fibers links the cytoskeleton to the extracellular matrix and with neuronal nitric oxide synthase. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan expression was detected in the caveolin-3-deficient patient. These results implicate an important function of the caveolin signature sequence and common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies with caveolin-3-deficient limb girdle muscular dystrophy.
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PMID:Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. 1100 38

Muscular dystrophies represent a heterogeneous group of disorders, which have been largely classified by clinical phenotype. In the last 10 years, identification of novel skeletal muscle genes including extracellular matrix, sarcolemmal, cytoskeletal, cytosolic, and nuclear membrane proteins has changed the phenotype-based classification and shed new light on the molecular pathogenesis of these disorders. A large number of genes involved in muscular dystrophy encode components of the dystrophin-glycoprotein complex (DGC) which normally links the intracellular cytoskeleton to the extracellular matrix. Mutations in components of this complex are thought to lead to loss of sarcolemmal integrity and render muscle fibers more susceptible to damage. Recent evidence suggests the involvement of vascular smooth muscle DGC in skeletal and cardiac muscle pathology in some forms of sarcoglycan-deficient limb-girdle muscular dystrophy. Intriguingly, two other forms of limb-girdle muscular dystrophy are possibly caused by perturbation of sarcolemma repair mechanisms. The complete clarification of these various pathways will lead to further insights into the pathogenesis of this heterogeneous group of muscle disorders.
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PMID:Molecular basis of muscular dystrophies. 1100 81


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