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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked recessive Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a membrane cytoskeletal protein. Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoprotein. The dystrophin-glycoprotein complex has been proposed to span the sarcolemma to provide a link between the subsarcolemmal cytoskeleton and the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a large reduction in all of the dystrophin-associated protein. We have investigated the possibility that a deficiency of a dystrophin-associated protein could be the cause of severe childhood autosomal recessive muscular dystrophy (SCARMD) with a DMD-like phenotype. Here we report the specific deficiency of the 50K dystrophin-associated glycoprotein (M(r) 50,000) in sarcolemma of SCARMD patients. Therefore, the loss of this glycoprotein is a common denominator of the pathological process leading to muscle cell necrosis in two forms of muscular dystrophy, DMD and SCARMD.
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PMID:Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy. 140 35

Dystrophin, the protein encoded by the Duchenne muscular dystrophy (DMD) gene, exists in a large oligomeric complex. We show here that four glycoproteins are integral components of the dystrophin complex and that the concentration of one of these is greatly reduced in DMD patients. Thus, the absence of dystrophin may lead to the loss of a dystrophin-associated glycoprotein, and the reduction in this glycoprotein may be one of the first stages of the molecular pathogenesis of muscular dystrophy.
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PMID:Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. 218 35

Marked deficiency of muscle adhalin, a 50 kDa sarcolemmal dystrophin-associated glycoprotein, has been reported in severe childhood autosomal recessive muscular dystrophy (SCARMD). This is a Duchenne-like disease affecting both males and females first described in Tunisian families. Adhalin deficiency has been found in SCARMD patients from North Africa Europe, Brazil, Japan and North America (SLR & KPC, unpublished data). The disease was initially linked to an unidentified gene on chromosome 13 in families from North Africa, and to the adhalin gene itself on chromosome 17q in one French family in which missense mutations were identified. Thus there are two kinds of myopathies with adhalin deficiency: one with a primary defect of adhalin (primary adhalinopathies), and one in which absence of adhalin is secondary to a separate gene defect on chromosome 13. We have examined the importance of primary adhalinopathies among myopathies with adhalin deficiency, and describe several additional mutations (null and missense) in the adhalin gene in 10 new families from Europe and North Africa. Disease severity varies in age of onset and rate of progression, and patients with null mutations are the most severely affected.
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PMID:Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity. 766 24

The C-terminal domain of dystrophin is alternatively spliced to produce a variety of tissue and developmental stage-specific isoforms. Recent studies suggest that the C-terminal domain binds to the dystrophin-associated glycoprotein complex (DGC) in muscle, but little is known about the functional significance of the alternative splicing or what role individual isoforms may play in specific tissues. The major dystrophin transcript in brain lacks exons 71-74, and encodes an isoform not observed in skeletal muscle. To explore the capacity of this truncated isoform to function in muscle, we have generated transgenic mice expressing a murine dystrophin mini-gene missing exons 71-74. Uniform expression of this construct on a mutant mdx mouse background results in normal muscle morphology and physiology, and prevents the development of muscular dystrophy. These mice also display normal expression and localization of the DGC, suggesting that the alternatively spliced exons are not required for dystrophin function in skeletal muscle. An additional line of mice was analyzed that had a mosaic pattern of expression. These mice display a markedly milder phenotype than mdx mice, despite the expression of dystrophin in only half the muscle fibers. These results indicate that viral delivery of dystrophin to a simple majority of fibers in a muscle group would greatly reduce the dystrophic pathology associated with Duchenne muscular dystrophy.
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PMID:Prevention of dystrophic pathology in mdx mice by a truncated dystrophin isoform. 784 95

We recently reported that the dystrophin-associated glycoprotein (DAG) complex is biochemically divided into two subcomplexes: one is the dystroglycan complex comprised of 156DAG and 43DAG and the other is the sarcoglycan complex comprised of 50DAG, A3b, and 35DAG. A3b is a novel dystrophin-associated glycoprotein with an approximate molecular mass of 43 kd but is distinct from 43DAG. In the present study, we examined the striated muscles of the dystrophic hamster with anti-A3b antibody in addition to anti-50DAG, anti-43DAG, anti-35DAG, anti-dystrophin, and anti-laminin antibodies by both immunohistochemistry and immunoblot analysis and found that 50DAG, A3b, and 35DAG are selectively lost. This selective defect of the sarcoglycan complex in dystrophic hamster muscles may give rise to dystrophic changes in striated muscles. Thus, the differentiation of the dystrophin-associated glycoprotein complex into the dystroglycan and sarcoglycan complexes is important not only from a biochemical standpoint but also in understanding the cause of muscular dystrophy in the hamster. Our findings further show that the dystrophic hamster may serve as an animal model for a human disease, severe childhood autosomal recessive muscular dystrophy, which has recently been shown to result from a selective defect in the sarcoglycan complex.
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PMID:Sarcoglycan complex is selectively lost in dystrophic hamster muscle. 785 62

The 50-kd dystrophin-associated glycoprotein (50DAG or adhalin) in the skeletal muscle has been shown to be deficient in patients with severe childhood autosomal recessive muscular dystrophy prevalent in North Africa. To elucidate the frequency of patients having the 50DAG deficiency in a muscular dystrophy population in Japan, we immunocytochemically examined 50DAG, 43DAG, dystrophin, and utrophin. A total of 243 patients with muscular dystrophy, among 1,035 diagnostic muscle biopsies during the past 2.5 years, were analyzed. We identified five unrelated patients (three females and two males who have no family history) with 50DAG deficiency in the sarcolemma. Thus, 2.1% (5/243) of our muscular dystrophy patient population had 50DAG deficiency.
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PMID:The frequency of patients with 50-kd dystrophin-associated glycoprotein (50DAG or adhalin) deficiency in a muscular dystrophy patient population in Japan: immunocytochemical analysis of 50DAG, 43DAG, dystrophin, and utrophin. 864 3

The expression of the 43 kDa dystrophin-associated glycoprotein (43DAG) has been studied using immunohistochemical labelling with a monoclonal antibody, MANDAG-1, and compared with immunolabelling for dystrophin and the dystrophin-related protein, utrophin, in normal muscle and in muscle from 50 patients with neuromuscular disease. 43DAG and dystrophin were expressed in vascular smooth muscle and at the sarcolemma of normal muscle fibres, with increased labelling at neuromuscular and myotendinous junctions. 43DAG expression was reduced in Duchenne and Becker dystrophies with patchy labelling, more intense around presumptive satellite cells. In Duchenne dystrophy, there was increased 43DAG expression in "revertant" fibres. In Becker dystrophy, 43DAG expression was more extensive around individual fibres, showed more interfibre variation and was more closely related to the intensity of immunolabelling for both dystrophin and utrophin than in Duchenne dystrophy. In other neuromuscular diseases, including congenital muscular dystrophy, no abnormalities of 43DAG expression were identified. The results suggest that in the absence of dystrophin, 43DAG is synthesized but is not stabilized in the sarcolemma. Stability is greater in Becker dystrophy but a normal dystrophin molecule appears to be required for the complete and stable membrane integration of 43DAG. Utrophin may confer some additional stability to the membrane integration of 43DAG but this is incomplete where dystrophin is absent or abnormal.
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PMID:Expression of the 43 kDa dystrophin-associated glycoprotein in human neuromuscular disease. 801 91

During the past year significant progress has been made in understanding how dystrophin deficiency leads to muscle cell necrosis in Duchenne muscular dystrophy and Becker muscular dystrophy. Dystrophin interacts with a glycoprotein complex spanning the muscle sarcolemma, effectively linking the actin cytoskeleton to the extracellular matrix. The carboxyl terminus of dystrophin is required for glycoprotein binding. Interestingly, at least three mRNAs transcribed from the distal end of the DMD gene in tissues other than muscle have been shown to encode this domain. Deficiency of a second component of the dystrophin-associated glycoprotein complex has been shown to occur in another muscle-wasting disorder, severe childhood autosomal recessive muscular dystrophy. Sequence analysis of the entire cDNA for the autosomal dystrophin-related protein utrophin has shown that dystrophin and utrophin are closely related. Furthermore, both of these proteins have been shown to bind to the same or a similar glycoprotein complex in muscle.
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PMID:Dystrophin and related proteins. 835 25

We have partially sequenced rabbit skeletal muscle gamma-sarcoglycan, an integral component of the dystrophin-glycoprotein complex. Specific antibodies were produced against a gamma-sarcoglycan peptide and used to examine the expression of gamma-sarcoglycan in skeletal muscle of patients with severe childhood autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by immunofluorescence and Western blotting that in skeletal muscle from these patients gamma-sarcoglycan is completely absent and alpha- and beta-sarcoglycan are greatly reduced in abundance, whereas other components of the DGC are preserved. In addition, we show that in normal muscle alpha-, beta-, and gamma-sarcoglycan constitute a tightly associated sarcolemma complex which cannot be disrupted by SDS treatment.
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PMID:Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12. 864 26

Recently, mutations in the genes encoding several of the dystrophin-associated proteins have been identified that produce phenotypes ranging from severe Duchenne-like autosomal recessive muscular dystrophy to the milder limb-girdle muscular dystrophies (LGMDs). LGMD type 2C is generally associated with a more severe clinical course and is prevalent in northern Africa. A previous study identified a single base pair deletion in the gene encoding the dystrophin-associated protein gamma-sarcoglycan in a number of Tunisian muscular dystrophy patients. To investigate whether gamma-sarcoglycan gene mutations cause autosomal recessive muscular dystrophy in other populations, we studied 50 muscular dystrophy patients from the United States and Italy. The muscle biopsies from these 50 patients showed no abnormality of dystrophin but did show diminished immunostaining for the dystrophin-associated protein alpha-sarcoglycan. Four patients with a severe muscular dystrophy phenotype were identified with homozygous, frameshifting mutations in gamma-sarcoglycan. Two of the four have microdeletions that disrupt the distal carboxyl-terminus of gamma-sarcoglycan yet result in a complete absence of gamma-and beta-sarcoglycan suggesting the importance of this region for stability of the sarcoglycan complex. This region of gamma-sarcoglycan, like beta-sarcoglycan, has a number of cysteine residues similar to those in epidermal growth factor cysteine-rich regions.
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PMID:Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy. 892 14


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