UNIPROT:Q00604 - FACTA Search

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Query: UNIPROT:Q00604 (X-linked)
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The regulation of utrophin, the autosomal homologue of dystrophin, has been studied in the canine X-linked model of Duchenne muscular dystrophy. Dystrophic muscle has been shown to exhibit abnormal sarcolemmal expression of utrophin, in addition to the normal expression at the neuromuscular junction, in peripheral nerves, vascular tissues and regenerating fibres. To establish whether this abnormal presence of utrophin in dystrophic muscle is a consequence of continued expression following regeneration, or is attributable to a disease related up-regulation, the expression of utrophin was compared immunocytochemically with that of dystrophin, beta-spectrin and neonatal myosin in regenerating normal and dystrophic canine muscle, following necrosis induced by the injection of venom from the snake Notechis iscutatis. In normal regenerating muscle, sarcolemmal utrophin and dystrophin were detected concomitantly from 2-3 d post-injection, prior to the expression of beta-spectrin. Down-regulation of utrophin was apparent in some fibres from 7 d, and it was no longer present on the extra-junctional sarcolemma by 14 d. Neonatal myosin was still present in all fibres at this stage, but dystrophin and beta-spectrin had been fully restored. In dystrophic regenerating muscle, down-regulation of utrophin occurred from 7 d, although it persisted on some fibres until 28 d, longer than in normal muscle. At 42 d, however, utrophin in dystrophic muscle was only detected in a population of small fibres thought to represent a second cycle of regeneration, with no immunolabelling of mature fibres.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of utrophin (dystrophin-related protein) during regeneration and maturation of skeletal muscle in canine X-linked muscular dystrophy. 780 86

Duchenne muscular dystrophy is a prevalent X-linked neuromuscular disease for which there is currently no cure. Recently, it was demonstrated in a transgenic mouse model that utrophin could functionally compensate for the lack of dystrophin and alleviate the muscle pathology (Tinsley, J. M., Potter, A. C., Phelps, S. R., Fisher, R., Trickett, J. I., and Davies, K. E. (1996) Nature 384, 349-353). In this context, it thus becomes essential to determine the cellular and molecular mechanisms presiding over utrophin expression in attempts to overexpress the endogenous gene product throughout skeletal muscle fibers. In a recent study, we showed that the nerve exerts a profound influence on utrophin gene expression and postulated that nerve-derived trophic factors mediate the local transcriptional activation of the utrophin gene within nuclei located in the postsynaptic sarcoplasm (Gramolini, A. O., Dennis, C. L., Tinsley, J. M., Robertson, G. S., Davies, K. E, Cartaud, J., and Jasmin, B. J. (1997) J. Biol. Chem. 272, 8117-8120). In the present study, we have therefore focused on the effect of agrin on utrophin expression in cultured C2 myotubes. In response to Torpedo-, muscle-, or nerve-derived agrin, we observed a significant 2-fold increase in utrophin mRNAs. By contrast, CGRP treatment failed to affect expression of utrophin transcripts. Western blotting experiments also revealed that the increase in utrophin mRNAs was accompanied by an increase in the levels of utrophin. To determine whether these changes were caused by parallel increases in the transcriptional activity of the utrophin gene, we transfected muscle cells with a 1. 3-kilobase pair utrophin promoter-reporter (nlsLacZ) gene construct and treated them with agrin for 24-48 h. Under these conditions, both muscle- and nerve-derived agrin increased the activity of beta-galactosidase, indicating that agrin treatment led, directly or indirectly, to the transcriptional activation of the utrophin gene. Furthermore, this increase in transcriptional activity in response to agrin resulted from a greater number of myonuclei expressing the 1.3-kilobase pair utrophin promoter-nlsLacZ construct. Deletion of 800 base pairs 5' from this fragment decreased the basal levels of nlsLacZ expression and abolished the sensitivity of the utrophin promoter to exogenously applied agrin. In addition, site-directed mutagenesis of an N-box motif contained within this 800-base pair fragment demonstrated its essential contribution in this regulatory mechanism. Finally, direct gene transfer studies performed in vivo further revealed the importance of this DNA element for the synapse-specific expression of the utrophin gene along multinucleated muscle fibers. These data show that both muscle and neural isoforms of agrin can regulate expression of the utrophin gene and further indicate that agrin is not only involved in the mechanisms leading to the formation of clusters containing presynthesized synaptic molecules but that it can also participate in the local regulation of genes encoding synaptic proteins. Together, these observations are therefore relevant for our basic understanding of the events involved in the assembly and maintenance of the postsynaptic membrane domain of the neuromuscular junction and for the potential use of utrophin as a therapeutic strategy to counteract the effects of Duchenne muscular dystrophy.
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PMID:Muscle and neural isoforms of agrin increase utrophin expression in cultured myotubes via a transcriptional regulatory mechanism. 942 25

5'-mutations in the dystrophin gene can result in cardiomyopathy without clinically-apparent skeletal myopathy. The effect of dystrophin mutations on the assembly and stability of the dystrophin associated protein (DAP) complex in human heart are not fully understood. The molecular defect in the dystrophin complex was explored in a family with an X-linked pedigree and severe dilated cardiomyopathy. Dystrophin gene analysis demonstrated a 5' duplication involving exons 2-7, which encodes the N-terminal actin binding domain of dystrophin. Ribonuclease protection and PCR assays demonstrated a reduction in muscle promoter transcribed dystrophin mRNA in the heart compared to skeletal muscle. A deficiency of cardiac dystrophin protein was observed by Western blot and lack of membrane localization by immunocytochemistry. The cardiac expression of the dystrophin related protein utrophin was increased, and the 43 kDa (beta-dystroglycan), 50 kDa (alpha-sarcoglycan) and 59 kDa (syntrophin) dystrophin associated proteins (DAPs) were co-isolated and present in nearly normal amounts in the membrane. However, cardiac dystrophin deficiency and increased utrophin expression were associated with loss of extracellular 156 kDa dystrophin associated glycoprotein (alpha-dystroglycan) binding to the cardiomyocyte membrane. alpha-Dystroglycan is responsible for linkage of the dystrophin complex to the extracellular matrix protein laminin. Therefore, 5' dystrophin mutations can reduce cardiac dystrophin mRNA, protein expression, and dystrophin function in X-linked cardiomyopathy (XLCM). The presence of membrane-associated beta-dystroglycan, alpha-sarcoglycan, syntrophin, and utrophin are insufficient to maintain cardiac function. This XLCM family has a 5' dystrophin gene mutation resulting in cardiac dystrophin deficiency and a loss of alpha-dystroglycan membrane binding.
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PMID:A 5' dystrophin duplication mutation causes membrane deficiency of alpha-dystroglycan in a family with X-linked cardiomyopathy. 944 25

Myotubular myopathy frequently presents in male infants with severe generalised muscular hypotonia and weakness associated with ventilatory insufficiency, and is diagnosed on biopsy by the presence of many fibres with central nuclei and mitochondrial aggregation. In a 6-year period, we have investigated five unrelated patients with clinical and pathological features suggesting an X-linked myotubular myopathy, including one female patient. In one male infant, a biopsy of vastus lateralis showed less than 2% centrally-nucleated fibres, while biceps brachii showed up to 15% centrally-nucleated fibres. Immunohistochemical expression of the neural cell adhesion molecule (CD56) was more intense in the biceps muscle than in vastus lateralis, while expression of desmin and vimentin was similar. Morphometric evaluation of tissue from each of the patients revealed a wide spread of values for the number of centrally-nucleated fibres per microscopic field, and variation in the extent of immunohistochemical expression of NCAM, utrophin, laminin alpha 5 chain, vimentin and HLA1 antigen. These variations in the manifestations of myotubular myopathy have not been previously described, and will need to be correlated with the increasing knowledge of the mutations in the MTM1 gene coding for myotubularin.
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PMID:Myotubular myopathy: morphological, immunohistochemical and clinical variation. 963 95

The X-linked muscle wasting disease Duchenne muscular dystrophy is caused by the lack of dystrophin in muscle. Protein structure predictions, patient mutations, in vitro binding studies and transgenic and knockout mice suggest that dystrophin plays a mechanical role in skeletal muscle, linking the subsarcolemmal cytoskeleton with the extracellular matrix through its direct interaction with the dystrophin-associated protein complex (DAPC). Although a signaling role for dystrophin has been postulated, definitive data have been lacking. To identify potential non-mechanical roles of dystrophin, we tested the ability of various truncated dystrophin transgenes to prevent any of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and the dystrophin-related protein utrophin. We show that restoration of the DAPC with Dp71 does not prevent the structural abnormalities of the post-synaptic membrane or the abnormal oxidative properties of utrophin/dystrophin-deficient muscle. In marked contrast, a dystrophin protein lacking the cysteine-rich domain, which is unable to prevent dystrophy in the mdx mouse, is able to ameliorate these abnormalities in utrophin/dystrophin-deficient mice. These experiments provide the first direct evidence that in addition to a mechanical role and relocalization of the DAPC, dystrophin and utrophin are able to alter both structural and biochemical properties of skeletal muscle. In addition, these mice provide unique insights into skeletal muscle fiber type composition.
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PMID:Dystrophin and utrophin influence fiber type composition and post-synaptic membrane structure. 1081 17

Duchenne muscular dystrophy (DMD) is the most prevalent inherited muscle disease and results from mutations/deletions in the X-linked dystrophin gene. Although several approaches have been envisaged to counteract the effects of this progressive disease, there is currently no cure available. One strategy consists in utilizing a protein normally expressed in DMD muscle which, once expressed at appropriate levels and at the correct subcellular location, could compensate for the lack of dystrophin. A candidate for such a role is the dystrophin-related protein now referred to as utrophin. In contrast to dystrophin, which is expressed along the length of healthy muscle fibers, utrophin accumulates at the neuromuscular junction in both normal and DMD fibers. Several years ago, we began a series of experiments to determine the mechanisms responsible for the expression of utrophin at the neuromuscular synapse. Initially, we showed that utrophin transcripts accumulate preferentially within the postsynaptic sarcoplasm. To determine whether selective transcription of the utrophin gene accounts for this synaptic accumulation of utrophin mRNAs, we injected several utrophin promoter-reporter constructs directly into mouse muscle and demonstrated the preferential synaptic expression of the reporter gene. These results suggested that local transcriptional activation of the utrophin gene is responsible for the accumulation of utrophin mRNAs at the neuromuscular junction. In these studies, we also demonstrated that an N-box motif contained within the utrophin promoter plays a critical role in directing the synapse-specific expression of the utrophin gene. Additionally, our studies have shown that the ets-factors GABP alpha and beta are part of a protein complex that can bind to the N-box motif to transactivate the gene in muscle cells in culture and in vivo. In these experiments, we also noted that the nerve-derived trophic factors agrin and ARIA/heregulin regulate expression of utrophin via the activation of GABP alpha and beta which in turn, transactivate the utrophin gene via the N-box motif. Although these studies demonstrate that transcriptional activation can regulate utrophin mRNA levels, it is possible that additional mechanisms are also involved. In particular, the association of mRNAs with cytoskeletal elements and RNA-binding proteins may contribute to the accumulation of utrophin transcripts within the postsynaptic sarcoplasm. In recent studies, we have begun to examine this and we have now identified specific regions within the 3' untranslated region that are necessary for targeting and stabilizing utrophin mRNAs in skeletal muscle cells. A series of in vivo studies have also led us to conclude that post-transcriptional mechanisms are indeed important in regulating the abundance of utrophin transcripts in muscle. Together, these studies should lead to the identification of cis- and trans-acting elements regulating transcription of the utrophin gene as well as the stability and targeting of its mRNA in muscle cells. The results should therefore, identify specific targets that may become important in designing specific pharmacological interventions directed at increasing the expression of utrophin into extrasynaptic regions of DMD muscle fibers. In addition, these findings will contribute to our basic understanding of the cellular and molecular events involved in the formation, maintenance and plasticity of the neuromuscular synapse.
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PMID:Multiple regulatory events controlling the expression and localization of utrophin in skeletal muscle fibers: insights into a therapeutic strategy for Duchenne muscular dystrophy. 1175 81

Duchenne muscular dystrophy (DMD) is an X-linked lethal disorder caused by a defect in the DMD gene, which encodes the cytoskeletal protein dystrophin. Utrophin is an autosomal homolog of the DMD gene product dystrophin, and augmented expression of endogenous utrophin is expected to provide an alternative therapeutic approach to DMD. We previously reported that an immune response against a beta-galactosidase-expressing adenovirus vector, AxCALacZ, resulted in an accumulation of endogenous utrophin on the extrasynaptic sarcolemma in dystrophin-deficient mdx mice. To determine which cytokine is involved in the regulation of utrophin expression, we directly injected several cytokines separately into neonatal mdx muscles and tested whether the expression of utrophin is increased on the sarcolemma. Importantly, among the cytokines tested, solely interleukin 6 (IL-6) successfully increased expression of utrophin. Moreover, the increase in utrophin mRNA was detected in recombinant IL-6-injected mdx muscles by quantitative real-time reverse transcriptase-polymerase chain reaction. Further, IL-6 expression was elevated in AxCALacZ-infected mdx muscle at an early stage, and anti-IL-6 receptor (IL-6R) antibody treatment blocked enhanced utrophin expression in AxCALacZ-infected mdx muscle. We should point out, however, that overexpression of utrophin due to recombinant IL-6 treatment lasted only 1 week. In addition, expression of utrophin was not evident in normal C57BL/10 neonatal muscles injected with IL-6. Taken together, these results suggest that IL-6 can induce overexpression of utrophin on the extrasynaptic sarcolemma but requires preexisting factors in neonatal mdx muscle to fully regulate utrophin expression.
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PMID:Interleukin 6 induces overexpression of the sarcolemmal utrophin in neonatal mdx skeletal muscle. 1187 29

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.
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PMID:Function and genetics of dystrophin and dystrophin-related proteins in muscle. 1191 91

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

There is a pressing need to develop new therapeutic approaches to Duchenne muscular dystrophy, an X-linked fatal disease primarily affecting skeletal and cardiac muscle. Gene therapy is an approach that has attracted much interest since the description of the Duchenne muscular dystrophy gene and its mutations in 1987. Since 1990 numerous reporter and dystrophin gene transfer studies have been conducted on muscles of animals but mostly in mice. Experimental protocols have ranged from germ-line gene transfer (via the production of transgenics) to somatic gene transfer studies using viral or non-viral vectors. But what have we actually learned from such studies that can be applied to patients with Duchenne muscular dystrophy? Various dystrophin, utrophin and integrin recombinant cDNAs have been shown to prevent the development of muscular dystrophy in transgenic dystrophic (mdx) mice. Somatic gene transfer prior to the onset of pathology have been shown to prevent the development of the muscular dystrophy in the mdx mouse but the data is less convincing for the beneficial effects of somatic gene transfer following the establishment of pathology. The time of onset and the course of the disease differ substantially between mouse and man and raise concerns about the applicability of gene therapy in man where the disease manifests in utero and the progression is more severe. The other major concern relates to uncertainty over the efficiency of the different vectors in man, particularly as many patients are likely to have encountered the infectious forms of the viruses that are proposed as vectors.
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PMID:Gene transfer studies in animals: what do they really tell us about the prospects for gene therapy in DMD? 1220 90

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