Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to gain an insight into the pathogenesis of mouse muscular dystrophy, we investigated the natural suppressor serine tRNA. The natural suppressor seryl-tRNA was distinguished from the other seryl-tRNAs on the basis of its specific property of being converted into phosphoseryl-tRNA by a tRNA kinase. On a wet-weight basis, the content of total tRNA in dystrophic muscles was 47% of that in normal muscles. Although the serine-accepting activities of tRNA were similar in muscles of 3-month-old dystrophic and normal mice, the ratio of [32P]phosphoseryl-tRNA (suppressor tRNA) to the total serine tRNA was significantly enhanced in dystrophic muscles compared with that in normal muscles. This high content of suppressor tRNA in dystrophic muscles was further confirmed by dot-blot hybridization experiments with the DNA probes CGTAGTCGGCAGGAT and CGCCCGAAAGGTGGAA for major tRNA(IGASer) and suppressor tRNA respectively. At the early postnatal age of 3 weeks, when only a week had elapsed since the first manifestation of the dystrophic symptom (hindleg dragging), the ratio of suppressor tRNA to major tRNAs in dystrophic hindleg muscles was abnormally increased. Thereafter it decreased with age in normal mice but remained almost unchanged in dystrophic mice. Consequently, at 3 months old, it was 1.7 times higher in dystrophic than in normal mice. The suppressor tRNA is now accepted to play a role in the synthesis of glutathione peroxidase. The present study showed that the content of this enzyme was abnormally elevated in dystrophic mice. Previously we had demonstrated that the docosahexaenoic (C22:6) acid content in phospholipids was decreased, possibly resulting from the enhanced oxidative milieu caused by the dystrophic condition. Thus far, the findings suggest that an increase in the contents of suppressor tRNA and glutathione peroxidase in dystrophic muscle may have been secondarily induced by such a highly oxidative state in the dystrophic condition. However, it is difficult to exclude the possibility that the natural suppressor tRNA plays a primary role in the pathogenesis of muscular dystrophies.
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PMID:The high content of natural suppressor serine tRNA in dystrophic mouse muscle. 231 Mar 73

The present study was undertaken to elucidate further the enzymatic changes in dystrophic muscle using multivariate analysis. The activities of 14 kinds of enzymes, including 6 exopeptidases, 4 endopeptidases, beta-N-acetyl-D-glucosaminidase, phosphatase, esterase, and ribonuclease, were examined in forelimb and hindlimb muscles as well as in cardiac muscle of dystrophic mice and their controls. Two principal components identified from the enzymatic spectrum proved to be related especially to aminopeptidases and to serine proteinases, respectively. The enzymatic changes in forelimb muscle were very similar to those in hindlimb muscle when both were compared to those in cardiac muscle. The changes in aminopeptidases were unique to the limb muscles, whereas those of serine proteinases were unique to cardiac muscle of dystrophic mice. In the future, more attention should be focused on the role of exopeptidases in pathogenetic mechanisms of muscular dystrophy, because of the possibility that they play a major role in the initial stage of muscular dystrophy.
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PMID:A multivariate study on enzymatic changes in limb muscles and heart muscle of dystrophic mice. 367 74

We have been searching for enzyme inhibitors in culture filtrates of microbes and have found leupeptin, antipain, chymostatin, elastatinal, pepstatin, hydroxypepstatin, pepstanone and phosphoramidon as specific inhibitors of serine, thiol, carboxyl and metallo proteases. We found significant activities of aminopeptidases, phosphatase and esterase on surface membranes of various mammalian cells. We discovered bestatin, amastatin, forphenicine, esterastin and ebelactones A and B as specific inhibitors against these enzymes. These inhibitors were proved to bind to cells and modify immune responses. The usefulness of bestatin in cancer treatment has been suggested by clinical studies. It has been shown by several investigators that some endopeptidases such as Ca2+-activated neutral proteases and some other serine proteases may play important roles in muscular dystrophy. In addition to these endopeptidases, we found an abnormal increase in various enzyme activities in dystrophic mice and chickens. Especially, aminopeptidase activities are markedly increased. Moreover, its inhibitor bestatin became interesting on the aspects of its binding to cell surfaces. Bestatin and leupeptin which inhibit Ca2+-dependent protease showed some therapeutic effects against mouse dystrophy. Investigating enzyme activities in synovial fluid of patients with rheumatoid arthritis and osteoarthritis, we found increased activities of aminopeptidases, chymotrypsin-like enzyme, and phosphatase in rheumatoid arthritis but not in osteoarthritis. In chronic hemodialysis patients, RNase activity in serum is markedly elevated. Thus, enzyme inhibitors are increasing their potential usefulness in treatment of various diseases.
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PMID:The relationships between enzyme inhibitors and function of mammalian cells. 704 7

Aberrant expression of the dystrophin-associated protein complex is thought to underlie the pathogenesis of Duchenne dystrophy, Becker muscular dystrophy, and severe childhood autosomal recessive muscular dystrophy. Recently, our laboratory identified an agrin receptor from Torpedo electric organ postsynaptic membranes. It is a heteromer of 190- and 50-kDa subunits with similarity to two components of the dystrophin-associated protein complex of alpha- and beta-dystroglycan. We now confirm the relationship between the Torpedo agrin receptor and mammalian dystroglycans and provide further information about the structure of the alpha-dystroglycan-beta-dystroglycan complex. The sequences of three peptides from each Torpedo subunit were 69% identical to mammalian dystroglycans. An antiserum to mammalian beta-dystroglycan recognizes the Torpedo 50-kDa polypeptide. Additionally, like alpha-dystroglycan, the 190-kDa agrin receptor subunit binds laminin. Previous studies have indicated that alpha- and beta-dystroglycan arise by cleavage of a precursor protein. Tryptic peptide mapping of both subunits and amino-terminal sequencing of Torpedo beta-dystroglycan indicate a single cleavage site, corresponding to serine 654 of the mammalian dystroglycan precursor. Gel electrophoresis analysis indicates there is at least one intrachain disulfide bond in beta-dystroglycan. These results provide precise primary structures for alpha- and beta-dystroglycan.
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PMID:The alpha-dystroglycan-beta-dystroglycan complex. Membrane organization and relationship to an agrin receptor. 759 85

The WW domain is a structured protein module found in a wide range of regulatory, cytoskeletal, and signaling molecules. Its ligands contain proline-rich sequences, some of which show a core consensus of XPPXY that is critical for binding. In order to gain a better understanding of the molecular and biological functions of WW domains, we decided to predict their cognate ligands by searching databases for proteins containing the XPPXY consensus. Using several axioms that take into account evolutionary conservation and functional similarity, we have identified four groups of proteins representing candidate ligands that signal through known or unknown WW domains. These include viral Gag proteins, sodium channels, interleukin receptors, and a subgroup of serine/threonine kinases. In addition, we proposed that dystrophin and beta-dystroglycan bind through the WW-XPPXY link and that interference with this interaction could result in muscular dystrophy. Our study provides guidelines for experiments to probe the molecular and biological functions of the WW domain-ligand connection. Should these predictions be proven empirically, the results may have important ramifications for basic research and medicine.
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PMID:Towards prediction of cognate complexes between the WW domain and proline-rich ligands. 879 92

Calpain I (mu-calpain) and II (m-calpain) are well known calcium-activated neutral cysteine proteases. Many reports have shown that activation of calpain is related to cataract formation, neuronal degeneration, blood clotting, ischemic injuries, muscular dystrophy and cornified cell envelope (CE) formation. Here, we report that insoluble CE formation was reduced after treatment with calpain I inhibitor (N-acetyl-leucyl-leucyl-norleucinal) on normal human epidermal keratinocytes (NHEK), whereas serine and thiol protease inhibitors had no effect on the reduction of CE. When NHEK cells were confluent, keratinocytes were treated with various concentrations (0.5 microM-0.5 mM) of calpain I inhibitor or serine and thiol protease inhibitors under calcium induced differentiation. Insoluble CE formation was reduced about 90% in the 50 microM calpain inhibitor I treated group by day 9 of culture, whereas insoluble CE was reduced only 10% in the same condition. Interestingly TGase activity was blocked by 90% in the 0.5 mM calpain inhibitor treated group within 72 h, whereas TGase activity was retained by 80% in the 0.5 mM serine protease inhibitor treated group at 7 day treatment. Therefore it can be suggested that cysteine protease calpains might be responsible for the activation of the TGase 1 enzyme to complete insoluble CE formation during epidermal differentiation.
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PMID:Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1. 989 58

Sarcoglycanopathies, affecting the dystrophin-associated sarcoglycan (SG) complex, are a heterogeneous group of neuromuscular disorders. A subgroup of these disorders, limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive disorder, clinically manifested as an early onset, severe Duchenne-like muscular dystrophy. LGMD2C is caused by mutations in the gamma-SG gene, localized on 13q12. Recently, a number of mutations have been described in that gene, among which C283Y, a "private" Gypsy mutation (eight codons before the 3' end of the gene) is detected. In this article, we report on a single-strand conformation polymorphism (SSCP) method for fast C283Y mutation detection, using direct dry blood spot amplification. The method permits a large number of samples to be easily screened. To check heterozygote carriers of C283Y mutation among Gypsy population in Bulgaria, the SSCP analysis was applied on 400 Gypsy newborns from northeast Bulgaria. Our results show 2.25% of heterozygosity, which means that 1 in 50 Gypsies carries the mutation. Moreover, new SSCP migration patterns were detected that revealed two polymorphisms still unavailable in the literature. One of these changes was 984G-->A, leading to substitution of conserved serine at position 287 with asparagine and the second one is 1049C-->G at the 3' UTR (untranslated region). The present data could help the understanding the role of these sequences for the protein function.
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PMID:C283Y mutation and other C-terminal nucleotide changes in the gamma-sarcoglycan gene in the Bulgarian Gypsy population. 1044 57

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive or autosomal dominant progressive muscular dystrophy characterized by progressive muscle wasting and weakness with scapulo-humero-peroneal distribution, early contracture and cardiomyopathy with conduction block. The responsible gene for EDMD, designated as 'STA', has been mapped to Xq 28 and cloned. It encodes a serine-rich protein of 254-amino-acid, called 'emerin', localized in the inner nuclear rim. We performed genetic analysis of a 23-year-old male clinically diagnosed as EDMD and found a novel point mutation. Total RNA was extracted from skeletal muscle and reverse-transcription and polymerase chain reaction amplification was performed using a set of oligonucleotide primers between 5'-flanking site of exon 1 and exon 4. Our patient gave a smaller PCR product (about 30 bp) than normal control. The determined cDNA sequence revealed a deletion of 29 bp, spanning position 164 to 192 in exon 1. To clarify the mutant allele, we performed genomic DNA sequence. Genomic DNA sequence from the initiation of exon 1 to the upstream lesion of exon 2 confirmed a novel point mutation G to C, at nucleotide 197 in the donor splice site of intron 1. This point mutation may interfere with the correct splicing of the mRNA and cause frameshift, resulted in truncation of predicted protein by premature stop. We report a novel point mutation G to C, at nucleotide 197 in the intron 1 of STA gene corresponding the truncation of predicted protein, which differs from any of the previously reported mutations.
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PMID:[A novel splice-site mutation in the STA gene in a Japanese patient with Emery-Dreifuss muscular dystrophy]. 1068 37

Limb-girdle muscular dystrophy 1A (LGMD1A [MIM 159000]) is an autosomal dominant form of muscular dystrophy characterized by adult onset of proximal weakness progressing to distal muscle weakness. We have reported elsewhere a mutation in the myotilin gene in a large, North American family of German descent. Here, we report the mutation screening of an additional 86 families with a variety of neuromuscular pathologies. We have identified a new myotilin mutation in an Argentinian pedigree with LGMD1 that is predicted to result in the conversion of serine 55 to phenylalanine (S55F). This mutation has not been found in 392 control chromosomes and is located in the unique N-terminal domain of myotilin, only two residues from the T57I mutation reported elsewhere. Both T57I and S55F are located outside the alpha-actinin and gamma-filamin binding sites within myotilin. The identification of two independent pedigrees with the same disease, each bearing a different mutation in the same gene, has long been the gold standard for establishing a causal relationship between defects in a gene and the resultant disease. As a description of the second known pedigree with LGMD1A, this finding constitutes that gold standard of proof that mutations in the myotilin gene cause LGMD1A.
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PMID:myotilin Mutation found in second pedigree with LGMD1A. 1242 13

Transgenic mice that express dystroglycan containing a serine to alanine point mutation at the normal site of cleavage (DG(S654A)) in their skeletal muscles fail to express endogenously cleaved dystroglycan and have muscular dystrophy [Neuromusc. Disord., in press]. Dystrophic DG(S654A) muscles have reduced binding of antibodies, including VIA4-1, that recognize carbohydrate antigens on alpha dystroglycan, a finding similar to muscles in some forms of congenital muscular dystrophy. Here we describe one DG(S654A) transgenic line where VIA4-1 antibody binding is absent in skeletal muscle. In theory, the absence of this carbohydrate antigen should inhibit later glycosylation events that would occur on the structure or structures this antibody binds to. One such modification is likely to be the CT carbohydrate antigen, which is present on alpha dystroglycan in muscles overexpressing the CT GalNAc transferase [Dev. Biol. 242 (2002) 58]. To test the relationship between the VIA4-1 and CT carbohydrate antigens, we made DG(S654A)/CT GalNAc transferase (DG(S654A)/CT) transgenic mice. Surprisingly, dystroglycan was cleaved, and alpha dystroglycan was glycosylated with the VIA4-1 antigen, in DG(S654A)/CT muscles. In addition, muscles in DG(S654A)/CT transgenic mice had little or no evidence of muscular dystrophy when compared to DG(S654A) littermates. These experiments demonstrate that the CT GalNAc transferase can affect the post-translational processing of dystroglycan and the extent of muscular dystrophy even in muscles where the VIA4-1 antigen is not present.
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PMID:Overexpression of the CT GalNAc transferase inhibits muscular dystrophy in a cleavage-resistant dystroglycan mutant mouse. 1264 45


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