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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mechanistic definition of the dystrophic process is proposed, and the effects of growth factors vs. down-regulation of growth are critically analyzed. A conceptual scheme is presented to illustrate the steps leading to pathology, and various compensatory systems which ameliorate the pathology are examined, particularly in regards to the mdv mouse which is resistant to the deficiency of dystrophin, the main protein product of the Duchenne and Becker muscular dystrophy (DMD/BMD) gene. These compensatory systems are analyzed in terms of the differential resistance of fiber types to pathogenesis. The generation of a stable population of maturationally arrested centronucleated fibers which express the mature adult myosin isoforms is proposed to be the main strategy of mdx muscle to minimize apoptosis. Physiological properties of these fibers, such as utrophin expression, and high mitochondrial and endoplasmic reticulum content, together with probable increased glycerophosphorylcholine concentrations and facile access to the vascular system, are hypothesized to be instrumental in their resistance to pathogenesis. It is proposed that the major element that determines the susceptibility of most human muscles to the dystrophic process is their inability to arrest the maturation of regenerated fibers at the centronucleated stage with a concomitant expression of the adult myosins.
Mol Cell Biochem 1999 May
PMID:Mechanisms of resistance to pathogenesis in muscular dystrophies. 1039 79

The spontaneous up-regulation of utrophin, observed in dystrophin-deficient skeletal muscle fibers, may decrease the susceptibility of such fibers to necrosis. It has been reported that the utrophin-rescued double-mutant mdx mouse always develops a lethal cardiomyopathy. We report two patients with severe dilated cardiomyopathy due to dystrophin gene mutations: the first was a manifesting Duchenne muscular dystrophy carrier and the second a patient affected with moderate Becker muscular dystrophy. We studied their explanted heart specimen and/or endoImyocardial biopsies by immunohistochemistry and Western blot for both dystrophin and utrophin. Utrophin was found to be over-expressed in these specimens. Our results suggest that in these patients the up-regulation of utrophin in dystrophin-deficient cardiomyocytes was unable to prevent the development of life-threatening myocardial dysfunction. These findings seem to dampen the enthusiasm raised by the prospect of DMD treatment by utrophin rescue in skeletal muscle fibers, as the myocardium would still remain severely affected.
J Mol Cell Cardiol 1999 Aug
PMID:Could utrophin rescue the myocardium of patients with dystrophin gene mutations? 1042 48

Duchenne muscular dystrophy is a devastating neuromuscular disease caused by lack of the protein, dystrophin, in skeletal muscle and heart, although the biochemical mechanism by which dystrophin loss causes muscle dysfunction is unknown. Here we show that the dystrophin-deficient mdx mouse and a mouse lacking both dystrophin and the dystrophin-related protein, utrophin (dko), have abnormal electrocardiograms (ECGs). In skeletal muscle, dystrophin is normally associated with neuronal nitric oxide synthase (nNOS) at the sarcolemma. Consequently, we have measured NOS isoform activities in hearts from control, mdx and dko mice. In control mouse hearts, eNOS and nNOS activities increased by 120% and 47%, respectively, between 2 and 6 months of age. In mdx mice, myocardial nNOS activity was decreased by 60%, 84% and 80% at 2, 6 and 12 months of age, respectively. Similarly, hearts from dko mice showed a 65% decrease in nNOS activity compared to controls at 2 months of age. Endothelial NOS (eNOS) activity was not affected by dystrophin loss, but inducible NOS (iNOS) activity was seven-fold higher than control in the mdx mouse heart by 12 months of age. We conclude that lack of dystrophin in the mdx mouse results in abnormal ECGs that are associated with decreased myocardial nNOS and increased iNOS activities.
J Mol Cell Cardiol 1999 Oct
PMID:Decreased myocardial nNOS, increased iNOS and abnormal ECGs in mouse models of Duchenne muscular dystrophy. 1052 23

In striated muscle, the cytoskeletal protein dystrophin, the protein product of the Duchenne muscular dystrophy gene, is associated with a number of sarcolemmal glycoproteins to form a large oligomeric complex, the dystrophin-glycoprotein complex (DGC). Over the last 10 years, four of these sarcolemmal glycoproteins, alpha-, beta-, gamma- and delta-sarcoglycans, have been shown to form a distinct subcomplex, the sarcoglycan complex, in the DGC. Furthermore, the genetic defects of alpha-, beta-, gamma- and delta-sarcoglycans have been identified as the causes of four distinct forms of muscular dystrophies, which are now collectively called sarcoglycanopathy. Current studies are beginning to focus on the biological functions of the sarcoglycan complex and the molecular mechanism by which its dysfunction leads to muscle cell degeneration.
Cell Mol Biol (Noisy-le-grand) 1999 Sep
PMID:Sarcoglycan complex: a muscular supporter of dystroglycan-dystrophin interplay? 1054 73

We have developed five conventional duplex polymerase chain reaction (PCR) protocols on single lymphocytes and blastomeres from embryos, in order to analyse five exons commonly deleted in deletion-type Duchenne muscular dystrophy (DMD). The five DMD gene exons (17, 19, 44, 45 and 48) can be analysed in separate duplex PCR reactions together with the sex-determining region Y (SRY) gene which enables simultaneous gender assignment. We present here PCR amplification results from single lymphocytes isolated from a normal male (220 cells), a normal female (24 cells) and a male DMD patient (40 cells) carrying a deletion of exons 46-49 within the DMD gene. The method failed to produce a PCR signal for the SRY gene in 8/220 normal male cells (3.6%) and for a DMD exon in 0-4.5% of normal male cells. One negative control out of 112 was positive. When this method was used to analyse two blastomeres from each of five embryos, concordant results were obtained for each pair of blastomeres. All embryos produced signals for the DMD exon tested with four of the embryos found to be male and one female. This method is therefore suitable for preimplantation genetic diagnosis and will allow the transfer of healthy embryos (both male and female) in families carrying DMD gene deletions involving at least one of the five exons 17, 19, 44, 45 and 48.
Mol Hum Reprod 1999 Nov
PMID:Analysis of five Duchenne muscular dystrophy exons and gender determination using conventional duplex polymerase chain reaction on single cells. 1054 73

Utrophin is a large ubiquitously expressed cytoskeletal protein, homologous to dystrophin, the protein disrupted in Duchenne muscular dystrophy. The association of both proteins with the actin cytoskeleton is functionally important and is mediated by a domain at their N termini, conserved in members of the spectrin superfamily, including alpha-actinin, beta-spectrin and fimbrin. We present the structure of the actin-binding domain of utrophin in complex with F-actin, determined by cryo-electron microscopy and helical reconstruction, and a pseudo-atomic model of the complex, generated by docking the crystal structures of the utrophin domain and F-actin into the reconstruction. In contrast to the model of actin binding proposed for fimbrin, the utrophin actin-binding domain appears to associate with actin in an extended conformation. This conformation places residues that are highly conserved in utrophin and other members of the spectrin superfamily at the utrophin interface with actin, confirming the likelihood of this binding orientation. This model emphasises the importance of protein flexibility in modeling interactions and presents the fascinating possibility of a diversity of actin-binding mechanisms among related proteins.
J Mol Biol 2000 Mar 24
PMID:Structure of the utrophin actin-binding domain bound to F-actin reveals binding by an induced fit mechanism. 1071 14

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.
Hum Mol Genet 2000 May 22
PMID:Dystrophin and utrophin influence fiber type composition and post-synaptic membrane structure. 1081 17

Deletion mutations and linkage mapping have localized an X-linked retinitis pigmentosa locus to Xp21, and a disease gene (RPGR) has been characterized. However, mutations have not been identified in most families expected to segregate the disease at this locus. Here, a retina-specific mRNA transcript from the Duchenne muscular dystrophy gene is identified. Based on these data, it is hypothesized that the Duchenne muscular dystrophy gene may represent a second Xp21 site at which retinitis pigmentosa mutations occur.
Mol Genet Metab 2000 May
PMID:Is the Duchenne muscular dystrophy gene also an X-linked retinitis pigmentosa locus? 1083 35

Duchenne muscular dystrophy (DMD) is a lethal recessive disease caused by the absence of dystrophin in skeletal muscle, heart and other tissues. No cure is available at present for DMD. Here we describe a new strategy for the correction of dystrophin deficiency based on the transplantation of normal somite-derived cells into mdx mouse embryos. Somite-derived cells were isolated from E11.5 transgenic mouse embryos expressing the LacZ gene under the control of the muscle-specific desmin promoter and injected into the uterine circulation of pregnant mdx mice at gestational days E11.5-E17. Approximately 30% of the injected mdx embryos survived the procedure. Donor somite-derived cells were able to cross the placenta and migrate into host embryonic tissues. The pattern of donor cell distribution in host tissues depended on the gestational age of the transplanted embryos. Cells were found in hindlimb muscles, diaphragm, heart and ribs in E11.5 treated embryos and in the skull, ribs, vertebrae and lung of E15-E17 treated embryos. Normal dystrophin transcripts were detected in muscle and bone by RT-PCR. Histochemical analysis showed co-localization of LacZ and dystrophin expression in 5% of soleus and quadriceps muscle fibres and in 4% of heart myocytes of two of seven 8-week-old treated mdx mice.
Hum Mol Genet 2000 Jul 22
PMID:Transplacental injection of somite-derived cells in mdx mouse embryos for the correction of dystrophin deficiency. 1091 73

Myoblast transfer therapy (MTT) is a cell-mediated gene transfer method aimed at the restoration of normal dystrophin expression in Duchenne muscular dystrophy (DMD). Initial clinical MTT trials were conducted amid much controversy, as they were based on very few animal studies. Unfortunately, the trials were of little therapeutic benefit. As a result, there has been a renaissance of interest in experimental studies in animal models. In MTT, myoblasts are obtained by muscle biopsy from normal, i.e., dystrophin-positive, donors, expanded in culture, and injected directly into the muscles of dystrophic recipients. The major requirement for successful MTT is the survival of injected donor myoblasts in the host environment. However, a vast majority of donor cells fail to survive for more than 1 h after injection, and very few last beyond the first week. This review on the immunological aspects of MTT focuses in particular on the roles of specific components of the host immune response, the effects of tissue culture on donor cells, and strategies under development to circumvent the problem of donor myoblast death after injection in vivo.
Mol Ther 2000 Apr
PMID:Immunobiology and the future of myoblast transfer therapy. 1093 48


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