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

Dystrophin links the actin cytoskeleton to the dystroglycan complex in the plasma membrane as part of the linkage between the cytoskeleton and the extracellular matrix. Damage to or absence of dystrophin causes Duchenne or Becker muscular dystrophy. It has been proposed that elevating the levels of utrophin, a close homologue of dystrophin, may act as a therapy for these forms of muscular dystrophy. This requires that there is a close functional equivalence of these two proteins. In both utrophin and dystrophin, the main actin-binding region is at the N terminus. It is related to sequences found in a number of other proteins including alpha-actinin, spectrin and fimbrin. Recent structural and biochemical studies of these proteins have shown that although the method of binding to actin is broadly similar, there are significant differences. There are even differences between utrophin and dystrophin. These studies imply that some caution should be applied to claims that utrophin and dystrophin are completely functionally interchangeable. In this paper, I review studies that elucidate and compare the actin-binding function of utrophin and dystrophin, particularly those initiated in the laboratory of Dr. John Kendrick-Jones at the MRC in Cambridge.
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PMID:Structural comparison of actin binding in utrophin and dystrophin. 1138 92

Dystrophin and the dystrophin-associated protein complex (DAPC) have recently been implicated in cell signalling events. These proteins are ideally placed to transduce signals from the extracellular matrix (ECM) to the cytoskeleton. Here we show that beta-dystroglycan is tyrosine-phosphorylated in C2/C4 mouse myotubes. Tyrosine phosphorylation was detected by mobility shifts on SDS-polyacrylamide gels (SDS-PAGE) and confirmed by immunoprecipitation and two-dimensional gel electrophoresis. The potential functional significance of this tyrosine phosphorylation was investigated using peptide 'SPOTs' assays. Phosphorylation of tyrosine in the 15 most C-terminal amino acids of beta-dystroglycan disrupts its interaction with dystrophin. The tyrosine residue in beta-dystroglycan's WW-binding motif PPPY appears to be the most crucial in disrupting the beta-dystroglycan-dystrophin interaction. beta-dystroglycan forms the essential link between dystrophin and the rest of the DAPC. This regulation by tyrosine phosphorylation may have implications in the pathogenesis and treatment of Duchenne's muscular dystrophy (DMD).
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PMID:The interaction of dystrophin with beta-dystroglycan is regulated by tyrosine phosphorylation. 1149 20

The first reported female patient with the Fukuyama type of congenital muscular dystrophy associated with a lack of C-terminal domain of dystrophin is presented. Clinically, the patient had characteristic features and magnetic resonance imaging findings of Fukuyama muscular dystrophy. Dystrophin analysis revealed a lack of the C-terminal domain but preserved N-terminal and rod domains of dystrophin in biopsied muscle. Moreover, she had reduced expression of merosin, syntrophin, and beta-dystroglycan in the skeletal muscle. Reverse transcriptase-polymerase chain reaction analysis of mRNA in the patient's muscle illustrated a complete lack of exons 71-74 of the dystrophin gene. These deletions, which remove the beta-dystroglycan and syntrophin binding site, may cause changes in the function of both beta-dystroglycan and syntrophin in human muscle.
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PMID:Fukuyama muscular dystrophy associated with lack of C-terminal domain of dystrophin. 1151 13

In muscle, dystrophin anchors a complex of proteins at the cell surface which includes alpha-dystroglycan, beta-dystroglycan, syntrophins and dystrobrevins. Mutations in the dystrophin gene lead to muscular dystrophy and mental retardation. In contrast to muscle, little is known about the localization and the molecular interactions of dystrophin and dystrophin associated proteins (DAPs) in brain. In the present study, we show that alpha-dystroglycan and dystrophin are localized to large neurones in cerebral cortex, hippocampus, cerebellum and spinal cord. Furthermore, we show that dystroglycan is a member of three distinct dystrophin-containing complexes. Two of these complexes contain syntrophin and both dystrophin and syntrophin are enriched in post-synaptic densities. These data suggest that dystrophin and DAPs may have a role in the organization of CNS synapses. Interestingly, the enrichment for syntrophin in post-synaptic densities is not affected in mice mutant for all dystrophin isoforms. Thus in the brain, unlike in muscle, the association of syntrophin with dystrophin is not crucial for the DAP complex which suggests that it may be associated with other proteins.
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PMID:Dystroglycan contributes to the formation of multiple dystrophin-like complexes in brain. 1152 Sep 3

Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.
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PMID:An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. 1156 31

In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles of axons. The laminin receptor and the mechanism through which dysmyelination and impaired sorting occur are unknown. We describe mice in which Schwann cell-specific disruption of beta1 integrin, a component of laminin receptors, causes a severe neuropathy with impaired radial sorting of axons. beta 1-null Schwann cells populate nerves, proliferate, and survive normally, but do not extend or maintain normal processes around axons. Interestingly, some Schwann cells surpass this problem to form normal myelin, possibly due to the presence of other laminin receptors such as dystroglycan and alpha 6 beta 4 integrin. These data suggest that beta 1 integrin links laminin in the basal lamina to the cytoskeleton in order for Schwann cells to ensheath axons, and alteration of this linkage contributes to the peripheral neuropathy of congenital muscular dystrophy.
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PMID:Conditional disruption of beta 1 integrin in Schwann cells impedes interactions with axons. 1178 30

Alpha-dystroglycan is a component of the dystrophin-glycoprotein-complex, which is the major mechanism of attachment between the cytoskeleton and the extracellular matrix. Muscle-eye-brain disease (MEB) is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities and lissencephaly. We recently found that MEB is caused by mutations in the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) gene. POMGnT1 is a glycosylation enzyme that participates in the synthesis of O-mannosyl glycan, a modification that is rare in mammals but is known to be a laminin-binding ligand of alpha-dystroglycan. Here we report a selective deficiency of alpha-dystroglycan in MEB patients. This finding suggests that alpha-dystroglycan is a potential target of POMGnT1 and that altered glycosylation of alpha-dystroglycan may play a critical role in the pathomechanism of MEB and some forms of muscular dystrophy.
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PMID:Deficiency of alpha-dystroglycan in muscle-eye-brain disease. 1188 57

The alpha2-laminin subunit contributes to basement membrane functions in muscle, nerve, and other tissues, and mutations in its gene are causes of congenital muscular dystrophy. The alpha2 G-domain modules, mutated in several of these disorders, are thought to mediate different cellular interactions. To analyze these contributions, we expressed recombinant laminin-2 (alpha(2)beta(1)gamma(1)) with LG4-5, LG1-3, and LG1-5 modular deletions. Wild-type and LG4-5 deleted-laminins were isolated from medium intact and cleaved within LG3 by a furin-like convertase. Myoblasts adhered predominantly through LG1-3 while alpha-dystroglycan bound to both LG1-3 and LG4-5. Recombinant laminin stimulated acetylcholine receptor (AChR) clustering; however, clustering was induced only by the proteolytic processed form, even in the absence of LG4-5. Furthermore, clustering required alpha(6)beta(1) integrin and alpha-dystroglycan binding activities available on LG1-3, acting in concert with laminin polymerization. The ability of the modified laminins to mediate basement membrane assembly was also evaluated in embryoid bodies where it was found that both LG1-3 and LG4-5, but not processing, were required. In conclusion, there is a division of labor among LG-modules in which (i) LG4-5 is required for basement membrane assembly but not for AChR clustering, and (ii) laminin-induced AChR clustering requires furin cleavage of LG3 as well as alpha-dystroglycan and alpha(6)beta(1) integrin binding.
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PMID:Contributions of the LG modules and furin processing to laminin-2 functions. 1188 75

Duchenne muscular dystrophy (DMD) is a congenital X-linked myopathy caused by lack of dystrophin protein expression. In DMD, the expression of many dystrophin-associated proteins (DAPs) is reduced along the sarcolemmal membrane, but the same proteins remain concentrated at the neuromuscular junction where utrophin, a dystrophin homologue, is expressed [Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, K. D. & Campbell, K. (1992) Nature (London) 360, 588-591]. This outcome has led to the concept that ectopic expression of a "synaptic scaffold" of DAPs and utrophin along myofibers might compensate for the molecular defects in DMD. Here we show that transgenic overexpression of the synaptic CT GalNAc transferase in the skeletal muscles of mdx animals (mdx/CT) increases the expression of utrophin and many DAPs, including dystroglycans, sarcoglycans, and dystrobrevins, along myofibers. Protein expression of utrophin and DAPs was equal to or above that of wild-type mice. In addition, alpha-dystroglycan was glycosylated with the CT carbohydrate antigen in mdx/CT but not in mdx muscles. mdx/CT mice have little or no evidence of muscular dystrophy by several standard measures; Serum creatine kinase levels, percentage of centrally located myofiber nuclei, and variance in myofiber diameter in mdx/CT muscles were dramatically reduced compared with mdx mice. These data suggest that ectopic expression of the CT GalNAc transferase creates a functional dystrophin-related complex along myofibers in the absence of dystrophin and should be considered as a target for therapeutic intervention in DMD.
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PMID:Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice. 1196 16

Mutations in dystrophin cause muscular dystrophy but also affect the CNS, including information processing in the retina. To better understand the molecular basis of these CNS deficits, we analyzed the molecular composition and developmental appearance of dystrophin and of the dystrophin-associated protein complex (DPC) in the embryonic and adult avian retina. We detected a concentration of the DPC at the vitreal border and in the outer plexiform layer of the adult retina. At both locations the complex had a different molecular composition and different developmental expression pattern. At the vitreal border, the complex was composed of utrophin, alpha-dystrobrevin-1, and dystroglycan, and was present at all stages of retinal development even before neurogenesis and gliogenesis. On the other hand, the complex in the outer plexiform layer consisted of dystrophin, beta-dystrobrevin and dystroglycan. The distribution of this complex changed from a diffusely distributed to an aggregated form during development concomitant with synapse formation in the outer plexiform layer. Solubilization of the retinal extracellular matrix by intravitreal injection of collagenase resulted in a redistribution of the complex at the retinal vitreal border but had no influence on the distribution of the dystrophin-associated proteins in the outer plexiform layer. These results demonstrate two types of dystrophin-like complexes in the chick retina with differential molecular compositions, different anchorage to the extracellular matrix, and different developmental expression patterns, suggesting distinct functions for the DPC at both locations.
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PMID:Molecular diversity of the dystrophin-like protein complex in the developing and adult avian retina. 1198 13


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