Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In skeletal muscle, neuronal nitric oxide synthase (nNOS) is anchored to the sarcolemma via the dystrophin-glycoprotein complex. When dystrophin is absent, as in Duchenne muscular dystrophy patients and in mdx mice, nNOS is mislocalized to the interior of the muscle fiber where it continues to produce nitric oxide. This has led to the hypothesis that free radical toxicity from mislocalized nNOS may contribute to mdx muscle pathology. To test this hypothesis directly, we generated mice devoid of both nNOS and dystrophin. Overall, the nNOS-dystrophin null mice maintained the dystrophic characteristics of mdx mice. We evaluated the mice for several features of the dystrophic phenotype, including membrane damage and muscle morphology. Removal of nNOS did not alter the extent of sarcolemma damage, which is a hallmark of the dystrophic phenotype. Furthermore, muscle from nNOS-dystrophin null mice maintain the histological features of mdx pathology. Our results demonstrate that relocalization of nNOS to the cytosol does not contribute significantly to mdx pathogenesis.
Hum Mol Genet 1998 May
PMID:mdx muscle pathology is independent of nNOS perturbation. 953 86

Duchenne muscular dystrophy (DMD) is the most common of the human muscular dystrophies, affecting approximately 1 in 3500 boys. Most DMD patients die in their late teens or early twenties due to involvement of the diaphragm and other respiratory muscles by the disease. The primary abnormality in DMD is an absence of dystrophin, a 427 kd protein normally found at the cytoplasmic face of the muscle cell surface membrane. Based upon the predicted structure and location of the protein, it has been proposed that dystrophin plays an important role in providing mechanical reinforcement to the sarcolemmal membrane of muscle fibers. Therefore, dystrophin could help to protect muscle fibers from potentially damaging tissue stresses developed during muscle contraction. In the present paper, the nature of mechanical stresses placed upon myofibers during various forms of muscle contraction are reviewed, along with current lines of evidence supporting a critical role for dystrophin as a subsarcolemmal membrane-stabilizing protein in this setting. In addition, the implications of these findings for exercise programs and other potential forms of therapy in DMD are discussed.
Mol Cell Biochem 1998 Feb
PMID:The molecular basis of activity-induced muscle injury in Duchenne muscular dystrophy. 954 54

Utrophin is normally present exclusively in synaptic regions of skeletal muscle fibers, although it is expressed extrasynaptically in certain pathological situations, where it has been proposed to compensate for the absence of dystrophin in Duchenne muscular dystrophy patients and mdx mice. Recently there have been conflicting reports regarding the preferential expression of utrophin mRNA at the neuromuscular junction. Using in situ hybridization with RNA probes, we show a clear accumulation of autoradiographic labeling at more than 90% of neuromuscular junctions (identified by histochemical demonstration of cholinesterase activity). The intensity of this labeling is proportional to the number of junctional myonuclei in the section. Some clusters of labeling were found associated with nonmuscle nuclei (e.g., blood vessels, nerves), where utrophin is present. In addition, labeling for utrophin mRNA was associated with about 25% of extrajunctional myonuclei, where the protein is not present. The mean labeling per nucleus at junctional myonuclei was at least 10 times greater than at extrajunctional myonuclei. We discuss the possible regulatory mechanisms involved in the heterogeneous expression of utrophin mRNA in skeletal muscle.
Mol Cell Neurosci 1998 Apr
PMID:Utrophin mRNA expression in muscle is not restricted to the neuromuscular junction. 960 3

Deletions and point mutations in the gene encoding the cytoskeletal protein dystrophin and its isoforms cause either the severe progressive myopathy Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy (BMD), largely depending on whether the reading frame is lost or maintained respectively. Frameshift mutations tend to result in a lack of dystrophin at the sarcolemma, destabilization of the membrane and degeneration of skeletal muscle. The mdx mouse is a valuable animal model of DMD as it bears a nonsense point mutation in exon 23 of the murine DMD gene leading to an absence of dystrophin expression in the muscle sarcolemma and muscular dystrophy. This report represents a novel approach to correct dystrophin deficiency at the post-transcriptional level by transfection of muscle cells with antisense RNA. Essentially, 2'- O -methyl oligoribonucleotides (2'OMeRNA) were delivered to the nuclei of primary mdx myoblasts in culture. Dystrophin expression was observed in the sarcolemma of transfected mdx myotubes after transfection by an oligonucleotide complementary to the 3' splice site of murine dystrophin intron 22. Direct sequencing of RT-PCR products from these cells revealed precise splicing of exon 22 to exon 30, skipping the mutant exon and creating a novel in-frame dystrophin transcript. As patients with comparable in-frame internal deletions show relatively mild myopathic symptoms, this may in the future offer a therapeutic approach for DMD, as well as for other inherited disorders.
Hum Mol Genet 1998 Jul
PMID:Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. 961 64

X-linked dilated cardiomyopathy (XLDCM) is a clinical phenotype of dystrophinopathy which is characterized by preferential myocardial involvement without any overt clinical signs of skeletal myopathy. To date, several mutations in the Duchenne muscular dystrophy gene, DMD , have been identified in patients with XLDCM, but a pathogenic correlation of these cardiospecific mutations in DMD with the XLDCM phenotype has remained to be elucidated. We report here the identification of a unique de novo L1 insertion in the muscle exon 1 in DMD in three XLDCM patients from two unrelated Japanese families. The insertion was a 5'-truncated form of human L1 inversely integrated in the 5'-untranslated region in the muscle exon 1, which affected the transcription or the stability of the muscle form of dystrophin transcripts but not that of the brain or Purkinje cell form, probably due to its unique site of integration. We speculate that this insertion of an L1 sequence in DMD is responsible for some of the population of Japanese patients with XLDCM.
Hum Mol Genet 1998 Jul
PMID:Insertional mutation by transposable element, L1, in the DMD gene results in X-linked dilated cardiomyopathy. 961 70

Utrophin is normally present exclusively in synaptic regions of skeletal muscle fibers, although it is expressed extrasynaptically in certain pathological situations, where it has been proposed to compensate for the absence of dystrophin in Duchenne muscular dystrophy patients and mdx mice. Recently there have been conflicting reports regarding the preferential expression of utrophin mRNA at the neuromuscular junction. Using in situ hybridization with RNA probes, we show a clear accumulation of autoradiographic labeling at more than 90% of neuromuscular junctions (identified by histochemical demonstration of cholinesterase activity). The intensity of this labeling is proportional to the number of junctional myonuclei in the section. Some clusters of labeling were found associated with nonmuscle nuclei (e.g., blood vessels, nerves), where utrophin is present. In addition, labeling for utrophin mRNA was associated with about 25% of extrajunctional myonuclei, where the protein is not present. The mean labeling per nucleus at junctional myonuclei was at least 10 times greater than at extrajunctional myonuclei. We discuss the possible regulatory mechanisms involved in the heterogeneous expression of utrophin mRNA in skeletal muscle. Copyright 1998 Academic Press.
Mol Cell Neurosci 1998 Apr
PMID:Utrophin mRNA Expression in Muscle Is Not Restricted to the Neuromuscular Junction. 961 15

The use of preimplantation diagnosis for sex determination and detection of exon deletion means that unaffected babies can be born to parents suffering from Duchenne muscular dystrophy (DMD). However, those who do not have exon deletion should also be considered for further investigation. A new method, known as linkage analysis, has been developed to diagnose the presence of non-deletion DMD in preimplantation embryos. Linkage analysis uses informative intragenic and flanking markers to track the chromosome bearing the mutated gene. The present study reports the analysis of two polymorphic sites, in blastomeres biopsied from embryos from a female carrier of DMD. A single male embryo was obtained who had inherited alternate maternal alleles to the woman's affected surviving son, and this embryo was transferred.
Mol Hum Reprod 1998 Apr
PMID:Preimplantation diagnosis of non-deletion Duchenne muscular dystrophy (DMD) by linkage polymerase chain reaction analysis. 962 Aug 34

The mdx mouse, an animal model of the Duchenne muscular dystrophy, was used for the investigation of changes in mitochondrial function associated with dystrophin deficiency. Enzymatic analysis of skeletal muscle showed an approximately 50% decrease in the activity of all respiratory chain-linked enzymes in musculus quadriceps of adult mdx mice as compared with controls, while in cardiac muscle no difference was observed. The activities of cytosolic and mitochondrial matrix enzymes were not significantly different from the control values in both cardiac and skeletal muscles. In saponin-permeabilized skeletal muscle fibers of mdx mice the maximal rates of mitochondrial respiration were about two times lower than those of controls. These changes were also demonstrated on the level of isolated mitochondria. Mdx muscle mitochondria had only 60% of maximal respiration activities of control mice skeletal muscle mitochondria and contained only about 60% of hemoproteins of mitochondrial inner membrane. Similar findings were observed in a skeletal muscle biopsy of a Duchenne muscular dystrophy patient. These data strongly suggest that a specific decrease in the amount of all mitochondrial inner membrane enzymes, most probably as result of Ca2+ overload of muscle fibers, is the reason for the bioenergetic deficits in dystrophin-deficient skeletal muscle.
Mol Cell Biochem 1998 Jun
PMID:Impaired mitochondrial oxidative phosphorylation in skeletal muscle of the dystrophin-deficient mdx mouse. 965 82

The neuronal nitric oxide synthase isoform nNOSmu, which is expressed in striated muscle, differs from nNOSalpha, the major brain isoform, by the insertion of 34 amino acid residues between the calmodulin- and flavin-binding domains [J Biol Chem 271:11204-11208 (1996)]. We show here that recombinant, purified nNOSmu, despite the peptide insertion, has the same spectroscopic properties, L-arginine kcat and Km values, optimal pH, and calmodulin binding affinity constant as nNOSalpha. However, nNOSmu consumes NADPH and reduces cytochrome c at approximately half the rate of nNOSalpha. The rates of degradation of the two proteins by rat brain and muscle homogenates show that nNOSmu is degraded more slowly than nNOSalpha. The in vitro half-lives of nNOSalpha and nNOSmu are 12 and 50 min, respectively, and calpain is important for this degradation. These short in vitro half-lives suggest that the nNOS isoforms are susceptible to rapid degradation in vivo. The elevated (20-fold) levels of calpain in diseased muscle tissue in Duchenne muscular dystrophy, and the hydrolytic sensitivity of both nNOS mu and nNOSalpha to this enzyme, may contribute to the deficiency of nNOS activity in the diseased tissue.
Mol Pharmacol 1998 Aug
PMID:Neuronal nitric oxide synthase isoforms alpha and mu are closely related calpain-sensitive proteins. 968 72

The electroretinograms (ERGs) of patients with Duchenne muscular dystrophy and an allelic variant of the mdx mouse (mdxCv3) have been shown to be abnormal. Analysis of five allelic variants of the mdx mouse with mutations in the dystrophin gene has shown that there is a correlation between the position of the mutation and the severity of the ERG abnormality. Three isoforms are expressed in the retina: Dp427, Dp260 and Dp71. Using indirect immunofluorescence and isoform-specific antibodies on retinal sections from three allelic mdx mouse strains, we have examined the localization of each of the isoforms. We show that Dp71 expression does not overlap with Dp427 and Dp260 expression at the outer plexiform layer (OPL). Instead, Dp71 is localized to the inner limiting membrane (ILM) and to retinal blood vessels. Moreover, we show that Dp260 and Dp71 differ structurally at their respective C-termini. In addition, we find that the proper localization of the beta-dystroglycan is dependent upon both Dp260 at the OPL and Dp71 expression at the ILM. Thus, Dp260 and Dp71 are non-redundant isoforms that are located at different sites within the retina yet have a common interaction with beta-dystroglycan. Our data suggest that both Dp71 and Dp260 contribute distinct but essential roles to retinal electrophysiology.
Hum Mol Genet 1998 Sep
PMID:Localization of dystrophin isoform Dp71 to the inner limiting membrane of the retina suggests a unique functional contribution of Dp71 in the retina. 970 Jan 91


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