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

To fully understand genome function, the linear genome map must be integrated with a spatial map of chromosomes in the nucleus. Distinct nuclear addresses for a few human chromosomes have been described. Previously we have demonstrated that the gene-rich human chromosome 19 is located in a more central position in the nucleus than the similarly sized, but gene-poor, chromosome 18. To determine whether these two chromosomes are a paradigm for the organization of chromatin in the human nucleus, we have now analysed the nuclear organization of every human chromosome in diploid lymphoblasts and primary fibroblasts. We find that the most gene-rich chromosomes concentrate at the centre of the nucleus, whereas the more gene-poor chromosomes are located towards the nuclear periphery. In contrast, we find no significant relationship between chromosome size and position within the nucleus. Proteins of the nuclear membrane or lamina are candidates for molecules that might anchor regions of the genome at the nuclear periphery and it has been suggested that disruption of this organization may play a role in some disease pathologies. We show that the intranuclear organization of chromosomes is not altered in cells that lack the integral nuclear membrane protein emerin, from an individual with X-linked Emery--Dreifuss muscular dystrophy. This suggests that emerin is not necessary for localizing chromosomes at the nuclear periphery and that the muscular dystrophy phenotype in such individuals is not due to grossly altered nuclear organization of chromatin.
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PMID:The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. 1115 39

Dysferlin is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited, forms of muscular dystrophy designated Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B), respectively. The function of dysferlin is not defined. Caveolin-3 is another skeletal muscle membrane protein which is important in the formation of caveolae and whose mutations cause dominantly inherited limb girdle muscular dystrophy type 1C (LGMD1C). We report that dysferlin co-immunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. We also describe abnormal localization of dysferlin in muscles from patients with LGMD1C including novel missense mutation (T64P) in the human caveolin-3 gene (CAV3). The immunoprecipitation data are consistent with the parallel observation that dysferlin immunostaining is not normal in LGMD1C muscles. Amino acid sequence analysis of the dysferlin protein reveals seven sites that correspond to caveolin-3 scaffold-binding motifs, and one site that is a potential target to bind the WW domain of the caveolin-3 protein. This is the first description of a possible dysferlin interacting protein; it suggests the hypothesis that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae.
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PMID:The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. 1153 85

Mutations in dysferlin, a novel membrane protein of unknown function, lead to muscular dystrophy. Myoferlin is highly homologous to dysferlin and like dysferlin is a plasma membrane protein with six C2 domains highly expressed in muscle. C2 domains are found in a variety of membrane-associated proteins where they have been implicated in calcium, phospholipid, and protein-binding. We investigated the pattern of dysferlin and myoferlin expression in a cell culture model of muscle development and found that dysferlin is expressed in mature myotubes. In contrast, myoferlin is highly expressed in elongated "prefusion" myoblasts and is decreased in mature myotubes where dysferlin expression is greatest. We tested ferlin C2 domains for their ability to bind phospholipid in a calcium-sensitive manner. We found that C2A, the first C2 domain of dysferlin and myoferlin, bound 50% phosphatidylserine and that phospholipid binding was regulated by calcium concentration. A dysferlin point mutation responsible for muscular dystrophy was engineered into the dysferlin C2A domain and demonstrated reduced calcium-sensitive phospholipid binding. Based on these data, we propose a mechanism for muscular dystrophy in which calcium-regulated phospholipid binding is abnormal, leading to defective maintenance and repair of muscle membranes.
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PMID:Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains. 1195 63

The myodystrophy (myd) mutation arose spontaneously and has an autosomal recessive mode of inheritance. Homozygous mutant mice display a severe, progressive muscular dystrophy. Using a positional cloning approach, we identified the causative mutation in myd as a deletion within the Large gene, which encodes a putative glycosyltransferase with two predicted catalytic domains. By immunoblotting, the alpha-subunit of dystroglycan, a key muscle membrane protein, is abnormal in myd mice. This aberrant protein might represent altered glycosylation of the protein and contribute to the muscular dystrophy phenotype. Our results are discussed in the light of recent reports describing mutations in other glycosyltransferase genes in several forms of human muscular dystrophy.
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PMID:Mutation of Large, which encodes a putative glycosyltransferase, in an animal model of muscular dystrophy. 1241 3

Dystroglycan (DG) is an essential component of the dystrophin-glycoprotein complex, a molecular scaffold that links the extracellular matrix to the actin cytoskeleton. Dystroglycan protein is post-translationally cleaved into alpha dystroglycan, a highly glycosylated peripheral membrane protein, and beta dystroglycan, a transmembrane protein. Despite clear evidence of the importance of dystroglycan and its associated proteins in muscular dystrophy, the purpose of dystroglycan proteolysis is unclear. By introducing a point mutation at the normal site of proteolysis (serine 654 to alanine, DGS654A), we have created a dystroglycan protein that is severely inhibited in its cleavage. Transgenic expression of DGS654A in mouse skeletal muscles inhibited the expression of endogenously cleaved dystroglycan, while overexpression of wild type dystroglycan by similar amounts did not. DGS654A animals had increased serum creatine kinase activity and most muscles had increased numbers of central nuclei. Overexpression of wild type dystroglycan, by contrast, caused no dystrophy by these measures. Dystrophy in DGS654A muscles correlated with reduced binding of antibodies that recognize glycosylated forms of alpha dystroglycan. Lastly, neuromuscular junctions in DGS654A muscles were aberrant in structure. These data show that aberrant processing of the dystroglycan polypeptide causes muscular dystrophy and suggest that dystroglycan processing is important for the proper glycosylation of alpha dystroglycan.
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PMID:Inhibition of dystroglycan cleavage causes muscular dystrophy in transgenic mice. 1279 92

Miyoshi myopathy, caused by mutations in the membrane protein dysferlin, is the most common muscular dystrophy that presents in the posterior calves. Its onset is before the age of 30 years and it is associated with marked elevations of serum creatine kinase (CK). In contrast, little is known about calf myopathies with onset after the age of 30, and it is not clear whether such patients have a dysferlinopathy. We describe five patients with a myopathy predominantly affecting the calf muscles, with onset after the age of 30. Muscle tissue was analyzed by immunoblot for dystrophin and dysferlin. All five had normal dysferlin but one had a dystrophinopathy. Serum CK levels ranged from 3 to 15 times the upper limit of normal. In contrast, all of 13 patients presenting before age 30 with calf weakness had a dysferlinopathy. Thus, isolated calf atrophy and weakness with onset after age 30, and associated with serum CK levels that are only moderately elevated, represents a distinct myopathy phenotype. Most of these cases are sporadic, although the overall phenotype appears genetically heterogeneous and dysferlinopathy is uncommon.
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PMID:Late-onset distal muscular dystrophy affecting the posterior calves. 1450 16

The Large(myd) mouse has a loss-of-function mutation in the putative glycosyltransferase gene Large. Mutations in the human homolog (LARGE) have been described in a form of congenital muscular dystrophy (MDC1D). Other genes (POMT1, POMGnT1, fukutin, and FKRP) that encode known or putative glycosylation enzymes are also causally associated with human congenital muscular dystrophies. All these diseases are associated with hypoglycosylation of the membrane protein alpha-dystroglycan (alpha-DG) and consequent loss of extracellular ligand binding. Hence, they are termed dystroglycanopathies. A paralogous gene for LARGE (LARGE2 or GYLTL1B) may also have a role in DG glycosylation. Using database interrogation and reverse-transcriptase polymerase chain reaction (RT-PCR), we identified vertebrate orthologs of each of these LARGE genes in many vertebrates, including human, mouse, dog, chicken, zebrafish, and pufferfish. However, within invertebrate genomes, we were able to identify only single homologs. We suggest that vertebrate LARGE orthologs be referred to as LARGE1. RT-PCR, dot-blot, and northern analysis indicated that LARGE2 has a more restricted tissue-expression profile than LARGE1. Using epitope-tagged proteins, we show that both LARGE1 and LARGE2 localize to the Golgi apparatus. The high similarity between the LARGE paralogs suggests that LARGE2 may also act on DG. Overexpression of LARGE2 in mouse C2C12 myoblasts results in increased glycosylation of alpha-DG accompanied by an increase in laminin binding. Thus, there may be functional redundancy between LARGE1 and LARGE2. Consistent with this idea, we show that alpha-DG is still fully glycosylated in kidney (a tissue that expresses a high level of LARGE2 mRNA) of Large(myd) mutant mice.
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PMID:Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies. 1595 17

Primary deficiency of merosin causes a severe congenital muscular dystrophy (CMD) and a mouse dystrophy (dy/dy mouse). Also, its secondary deficiency is seen in some CMD with abnormal glycosylation of Alpha-dystroglycan, an extracellular membrane protein, which is the receptor of merosin and binds to dystrophin underlying the sarcolenma via Beta-dystroglycan, a transmembrane protein. In immunogold and freeze-etch electron microscopic studies, merosin in basal lamina of normal skeletal muscles has a zonation in the distribution and is localized at the lamina lucida of muscle basal lamina, and dystrophin molecules are often closed to merosin molecules at the inside and outside surface of muscle plasma membrane. Moreover, merosin molecules exist as the short fine cross-bridge fibrils connecting the basal lamina to the neighboring outer leaflet of the muscle plasma membrane. In freeze-fracture studies, the changes in muscle plasma membranes of dy/dy mice reveal a markedly decreased density of orthogonal arrays (OAs) but normal density of intramembranous particles (IMPs), whereas depletions of IMPs with decreased OAs have been found in Fukyama-type congenital muscular dystrophy, Duchenne muscular dystrophy, and mdx mice. Thus, further studies including the functional role of OAs would be required to understand the pathomechanism of merosin-deficient CMD.
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PMID:Merosin (laminin-2) localization in basal lamina of normal skeletal muscle fibers and changes in plasma membrane of merosin-deficient skeletal muscle fibers. 1622 54

The cardiomyocyte membrane cytoskeleton consists of the costameric proteins that mediate force transduction from the cell to the extracellular matrix, and a sub-membrane network composed of dystrophin and associated proteins. Studies of the precise cellular distribution of dystrophin and of the consequences of genetic mutations leading to abnormal expression of the dystrophin molecule, as occurs in Duchenne and Becker's muscular dystrophies, highlight potential functional roles of this sub-membrane protein complex in cardiomyocytes. Detailed investigation of dystrophin distribution using the complementary cell imaging techniques of immunoconfocal microscopy and freeze-fracture cytochemistry at the electron-microscopical level show that, in contrast to rat cardiomyocytes, the dystrophin network in human cardiomyocytes is locally enriched at costameres. Thus located, the dystrophin network appears to have a mechanical role, involving stabilization of the peripheral plasma membrane during the repetitive distortion associated with cardiac contraction and, in the human myocyte, contributing to lateral force-transduction. Evidence from animal models of muscular dystrophy and from investigation of the interactions of the sub-membrane cytoskeleton with other membrane-associated proteins including ion channels, receptors and enzymes, further suggests a role for dystrophin in organization and regulation of membrane domains. The relative preservation of the membrane cytoskeleton in non-dystrophic dilated cardiomyopathy and in ischemic cardiomyopathy, conditions in which the myocyte contractile apparatus and internal desmin-based cytoskeleton are commonly disrupted, emphasizes the vital role of the membrane cytoskeleton in cell survival. Continued cardiomyocyte survival despite loss of contractile protein organization has implications in the potential for reversibility of left ventricular remodeling that can be achieved in the clinical setting.
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PMID:Dystrophin and the cardiomyocyte membrane cytoskeleton in the healthy and failing heart. 1622 6

Duchenne muscular dystrophy is a lethal X-linked muscle disease resulting from a defect in the muscle membrane protein dystrophin. The absence of dystrophin leads to muscle membrane fragility, muscle death (necrosis) and eventual replacement of skeletal muscle by fat and fibrous connective tissue. Extensive muscle wasting and respiratory failure results in premature death often by the early 20s. This short review evaluates drug and nutritional interventions designed to reduce the severity of muscular dystrophy, while awaiting the outcome of research into therapies to correct the fundamental gene defect. Combinations of dietary supplementation with amino-acids such as creatine, specific anti-inflammatory drugs and perhaps drugs that target ion channels might have immediate realistic clinical benefits although rigorous research is required to determine optimal combinations of such interventions.
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PMID:Duchenne muscular dystrophy: focus on pharmaceutical and nutritional interventions. 1713 28


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