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)

Integrin alpha 7 beta 1 is a specific cellular receptor for the basement membrane protein laminin-1 (refs 1,2), as well as for the laminin isoforms -2 and -4 (ref. 3). The alpha 7 subunit is expressed mainly in skeletal and cardiac muscle and has been suggested to be involved in differentiation and migration processes during myogenesis. Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle. In adult muscle, the alpha 7A and alpha 7B subunits are concentrated in myotendinous junctions but can also be detected in neuromuscular junctions and along the sarcolemmal membrane. To study the potential involvement of alpha 7 integrin, during myogenesis and its role in muscle integrity and function, we generated a null allele of the alpha 7 gene (Itga7) in the germline of mice by homologous recombination in embryonic stem (ES) cells. Surprisingly, mice homozygous for the mutation are viable and fertile, indicating that the alpha 7 beta 1 integrin is not essential for myogenesis. However, histological analysis of skeletal muscle revealed typical symptoms of a progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The observed histopathological changes strongly indicate an impairment of function of the myotendinous junctions. These findings demonstrate that alpha 7 beta 1 integrin represents an indispensable linkage between the muscle fibre and the extracellular matrix that is independent of the dystrophin-dystroglycan complex-mediated interaction of the cytoskeleton with the muscle basement membrane.
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PMID:Absence of integrin alpha 7 causes a novel form of muscular dystrophy. 935 97

The classical form of congenital muscular dystrophy (CMD) is now classified into merosin-deficient and -positive forms. The merosin (laminin alpha 2) is one of three subunits of a muscle basement membrane protein, laminin. Patients with the merosin-deficient form have generalized muscle weakness and hypotonia from early infancy as seen in FCMD but with no significant central nervous system involvement. The serum creatine kinase (CK) is markedly elevated. Strikingly all patients examined by a CT/ MRI have diffuse white matter abnormalities mimicking leukodystrophy. The gene has been mapped to chromosome 6q2 in the coding region for merosin. Since the responsible gene and protein have not been identified in the merosin-positive form, this CMD is probably a group of heterogeneous diseases. The overall symptoms are mild, approximately 90% of patients learned to walk alone.
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PMID:[Non-Fukuyama type congenital muscular dystrophy--merosin deficient and positive forms]. 943 31

Walker-Warburg syndrome is an autosomal-recessive genetic disorder characterized by congenital muscular dystrophy in association with complex developmental abnormalities of the central nervous system and the eyes. Two patients with Walker-Warburg syndrome are presented to demonstrate clinical variability. Previously unreported pathologic findings involving heart, muscle, spinal cord, and gall bladder are described, and the literature is reviewed. Histopathologic studies of the muscle membrane protein network in both Walker-Warburg syndrome patients reveal a decreased immunostaining for laminin alpha2 and beta-dystroglycan. The clinical, histologic, and biochemical variability in Walker-Warburg patients may reflect heterogeneity.
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PMID:Walker-Warburg syndrome: neurologic features and muscle membrane structure. 949 98

Recent advances in molecular biology have indicated that many mutant animal models of muscular dystrophy share common genetic and protein abnormalities similar to those of the human disease. The best example is a model of Duchenne muscular dystrophy (DMD), the mdx mouse. Similar to dystrophic muscle in DMD patients, dystrophin protein is not expressed along the surface membrane, even though the mdx mouse has no apparent signs of muscular dysfunction. Because clinical and pathologic findings in the dystrophic (mxd) dog are similar to those in DMD patients, it also has been regarded as a good model for therapeutic trials. The best known and most extensively studied dy+dy+ mouse lacks merosin (laminin alpha2), which is one subunit of a basement membrane protein, laminin. Because approximately half of all patients with the classical form of congenital muscular dystrophy also lack merosin, availability of this animal has revived interest in the study of the pathologic mechanism of fiber necrosis resulting from this membrane defect. The dystrophic hamster is a model of limb-girdle muscular dystrophy with sarcoglycan deficiency in which one of the dystrophin-associated glycoproteins, delta-sarcoglycan, is defective. Because these animal models have common protein and genetic defects similar to those seen in people with muscular dystrophies, they have been widely used to examine the effectiveness of gene therapy and the administration of pharmacologic and trophic factors.
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PMID:Animal models of muscular dystrophies. 951 83

Plectin and its isoforms are versatile cytoskeletal linker proteins of very large size (>500 kDa) that are abundantly expressed in a wide variety of mammalian tissues and cell types. Earlier studies indicated that plectin molecules were associated with and/or directly bound to subcomponents of all three major cytoskeletal filament networks, the subplasma membrane protein skeleton, and a variety of plasma membrane-cytoskeleton junctional complexes, including those found in epithelia, various types of muscle, and fibroblasts. In conjunction with biochemical data, this led to the concept that plectin plays an important role in cytoskeleton network organization, with consequences for viscoelastic properties of the cytoplasm and the mechanical integrity and resistance of cells and tissues. Several recent findings lent strong support to this concept. One was that a hereditary disease, epidermolysis bullosa simplex (EBS)-MD, characterized by severe skin blistering combined with muscular dystrophy, is caused by defects in the plectin gene. Another was the generation of plectin-deficient mice by targeted inactivation of the gene. Dying shortly after birth, these animals exhibited severe defects in skin, skeletal muscle and heart. Moreover, in vitro studies with cells derived from such animals unmasked an essential new role of plectin as regulator of cellular processes involving actin stress fibers dynamics. Comprehensive analyses of the gene locus in man, mouse, and rat point towards a complex gene expression machinery, comprising an unprecedented diversity of differentially spliced transcripts with distinct 5' starting exons, probably regulated by different promoters. This could provide a basis for cell type-dependent and/or developmentally-controlled expression of plectin isoforms, exerting different functions through binding to distinct partners. Based on its versatile functions and structural diversification plectin emerges as a prototype cytolinker protein among a family of proteins sharing partial structural homology and functions.
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PMID:Role of plectin in cytoskeleton organization and dynamics. 970 47

Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD. Future gene therapies of human MCMD, and perhaps of other forms of muscular dystrophy, may require restoration of the defective gene product in multiple tissues.
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PMID:Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models. 971 Apr 54

The dy/dy mouse is an animal model for human merosin-negative congenital muscular dystrophy (CMD), which has been reported to have reduced or no expression of the basement membrane protein laminin alpha2. We here investigate various myogenic and nonmyogenic tissues of mature dy/dy and control 129ReJ mice histologically and for laminin alpha2 expression. In addition, expression patterns of laminin alpha1, alpha2, alpha4, and alpha5 chains, the interstitial proteins fibronectin and tenascin-C, and the adhesion molecules VCAM-1, ICAM-1, and alpha4 integrin were characterized in skeletal muscle of 1- and 7-day and mature (>6 weeks old) dy/dy and control 129ReJ mice. The laminin alpha2 chain remained detectable in myogenic tissues of dy/dy mice by immunofluorescence using two different monoclonal antibodies and by Northern blot analysis. However, laminin alpha2 expression was significantly reduced or not detectable in nonmyogenic tissues of dy/dy mice, including skin, lung, kidney, brain, thymus, and eye. Focal lesions were observed in mature skeletal muscle only, characterized by necrotic tissue, isolated VCAM-1- and ICAM-1-positive cells indicative of inflammatory processes, and regenerating muscle fibers surrounded by intense tenascin-C and fibronectin expression. In contrast to studies on human CMD muscle, laminin alpha1 was not detectable in either dy/dy or control skeletal muscle using immunofluorescence or Northern blot analysis. Immunofluorescence localized laminin alpha4 to basement membranes of blood vessels, the endoneurium of the intramuscular nerves, and the neuromuscular junction in skeletal muscle of 1- and 7-day-old dy/dy and control mice. In mature muscle, laminin alpha4 expression shifted to the perineurium of intramuscular nerves in both dy/dy and control mice. Furthermore, strong upregulation of laminin alpha4 in the basement membranes of blood vessels, the perineurium of intramuscular nerves, and of isolated regenerating muscle fibers in the dy/dy mice was apparent. Investigation of 1-day-old animals revealed expression of laminin alpha5 in skeletal muscle fiber basement membranes of dy/dy but not control animals. This difference between dy/dy and control animals was no longer apparent at 7 days after birth, indicating a temporary shift in expression pattern of laminin alpha5 in dy/dy animals. Analysis of the extracellular matrix components of 1- and 7-day-old dy/dy and control skeletal muscle revealed an early onset of the dystrophy, even before histopathological features of the disease were evident. Our data confirm the absence of laminin alpha1 chain in myogenic tissues of both dy/dy and control mice and suggest compensation for reduced laminin alpha2 in dy/dy skeletal muscle by laminin alpha4 and, in early development, also laminin alpha5. These results have significant ramifications in the diagnosis of human merosin-negative CMD.
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PMID:Expression of laminin alpha1, alpha2, alpha4, and alpha5 chains, fibronectin, and tenascin-C in skeletal muscle of dystrophic 129ReJ dy/dy mice. 988 26

Mutations in laminin alpha2, a subunit of the basement membrane protein laminin-2/merosin, cause merosin-deficient congenital muscular dystrophy. To gain insight into the molecular mechanism of disease, we generated and used a mutant mouse, dyW, in which the lacZ gene was inserted into the lama2 gene so that beta-galactosidase would be expressed in place of laminin alpha2. Heterozygous and homozygous mutant mice are normal at birth, but homozygous mice develop muscular dystrophy at 2 to 3 weeks of age. The lama2/lacZ gene was highly expressed in muscle in the early stages of embryonic myogenesis, but was down-regulated at later stages in both heterozygous and homozygous mice. No beta-galactosidase activity was detected in skeletal muscle after birth in adult heterozygous mice. In contrast, high beta-galactosidase activity was detected in postnatal homozygous mice. Induction of injury in heterozygous mice resulted in intense reexpression of beta-galactosidase in the injured muscle early in regeneration, with a decline in enzyme activity as repair of the tissue progressed. Although the initial response to injury was similar in heterozygous and homozygous mice with abundant beta-galactosidase-positive, mononucleated cells in the injured area, repair was rarely completed in the homozygous mice, evidently caused by excessive death of cells associated with immature myofibers. The defect in muscle repair was very efficiently corrected in homozygous dyW mice expressing a human LAMA2 transgene in skeletal muscle. The data show the importance of laminin alpha2 in muscle regeneration and suggest that a major contributor to disease in muscular dystrophy is abortive regeneration.
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PMID:Activation of the lama2 gene in muscle regeneration: abortive regeneration in laminin alpha2-deficiency. 1061 10

Emery-Dreifuss muscular dystrophy (EDMD) was delineated as a separate form of muscular dystrophy nearly 40 years ago, based on the distinctive clinical features of early contractures and humero-peroneal weakness, and cardiac conduction defects. The gene, STA at Xq28, for the commoner X-linked EDMD encodes a 34 kD nuclear membrane protein designated 'emerin', and in almost all cases on immunostaining is absent in muscle, skin fibroblasts, leucocytes and even exfoliative buccal cells, and a mosaic pattern in female carriers. The gene, LMNA at 1q21, for the autosomal dominant Emery-Dreifuss muscular dystrophy encodes other nuclear membrane proteins, lamins A/C. The diagnosis (at present) depends on mutation analysis rather than protein immunohistochemistry. It is still not at all clear how defects in these nuclear membrane proteins are related to the phenotype, even less clear that LMNA mutations can also be associated with familial dilated cardiomyopathy with no weakness, and even familial partial lipodystrophy with diabetes mellitus and coronary heart disease! What began as clinical studies in a relatively rare form of dystrophy has progressed to detailed research into the functions of nuclear membrane proteins particularly in regard to various forms of heart disease.
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PMID:Emery-Dreifuss muscular dystrophy - a 40 year retrospective. 1083 46

This lecture traces recent advances in knowledge of the muscular dystrophies, as well as their increasing complexity. They are described through the eyes of the author from his first exposure to and complete ignorance of the disease in the late 1950s, through the advent of modern techniques, to the molecular genetic revolution, with the recognition of individual genes and proteins for disorders within the muscular dystrophy umbrella. There initially seemed to be a logical sequence of linked membrane proteins from dystrophin in Duchenne and Becker dystrophy, through the dystrophin-associated glycoproteins (sarcoglycans) in some of the limb girdle muscular dystrophies (LGMD), to the extracellular matrix protein merosin (alpha-2 laminin) in congenital muscular dystrophy (CMD). The first spoke in the wheel came with the discovery of a calcium activated protease enzyme, calpain 3, in one form of LGMD, and subsequently another novel non-membrane protein, dysferlin, in another. There are currently at least eight distinct genetic forms of LGMD alone, and another eight separate genetic entities in the CMD group. This has highlighted our ignorance of the pathogenesis of the muscular dystrophies in relation to a diverse array of protein deficiencies. To compound things further, the X-linked and dominant forms of Emery-Dreifuss muscular dystrophy have recently been linked to emerin and lamin A/C, respectively, two proteins of the nuclear membrane, opening up yet another new ballpark of discovery.
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PMID:What is muscular dystrophy? Forty years of progressive ignorance. 1107 61


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