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At least 703 records · Page 39Linked to original sources
PubMed1989

Immunochemical study of connectin (titin) in neuromuscular diseases using a monoclonal antibody: connectin is degraded extensively in Duchenne muscular dystrophy.

Connectin (also called titin) is a myofibrillar elastic filament which links a thick filament to a neighbouring Z line in a sarcomere and thus contributes significantly to the elastic property of myofibrils. In the present study, the degradation state of connectin in biopsied skeletal muscles from various neuromuscular diseases was investigated by Western blot analysis using a monoclonal antibody which reacts extensively with the degradation products of connectin. In Duchenne muscular dystrophy (DMD), connectin was degraded progressively and relentlessly after 5 years of age. In Becker muscular dystrophy, degradation of connectin was much less than in DMD. Connectin was well preserved in normal controls, and was only minimally degraded in Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, limb girdle muscular dystrophy and myotonic dystrophy, even when the biopsied muscles showed a similar degree of weakness as those of DMD. The degradation of connectin, even though secondary, is presumed to play an important role in the pathogenesis of myofibrillar degeneration in DMD.

Adolescent↗
PubMed1990

Nature of the mononuclear infiltrate and the mechanism of muscle damage in juvenile dermatomyositis and Duchenne muscular dystrophy.

Normal skeletal muscle does not express class I MHC antigens. In contrast, these antigens are strongly expressed at the periphery of muscle fibres in patients with juvenile dermatomyositis (JDM) and Duchenne muscular dystrophy (DMD). Interferons can induce the expression of class I antigens, but in this study interferon-gamma could not be detected in JDM muscle biopsy specimens using four different immunocytochemical techniques. However, an infiltrate of mononuclear cells capable of synthesising interferons was present in biopsies from JDM and DMD patients. The predominant cell types detected in both diseases were macrophages and T lymphocytes, these two cell types comprising more than 80% of the infiltrating mononuclear cells. A striking predominance of CD4+ helper/inducer T cells was observed. The majority of these cells expressed class II MHC antigens and were, therefore, considered to be activated. Additional evidence for the functional activity of CD4+ T cells was derived from the finding that it was this population of cells from JDM biopsies which proliferated in response to interleukin-2 in vitro. T cell subsets in peripheral blood were also investigated in JDM and DMD patients. Only in the case of JDM were any significant differences from normal observed, where a significant reduction in the number of peripheral blood CD8+ T cells resulted in an elevation of CD4+/CD/8+ ratios. The role of CD4+ T cells and aberrant class I MHC antigen expression in mediating muscle damage in JDM and DMD is discussed.

CD4-Positive T-Lymphocytes↗
PubMed1991

Immunocytochemical analysis of dystrophin in congenital muscular dystrophy.

Using immunocytochemical methods, we examined the intensity and distribution of dystrophin and spectrin immunostaining of skeletal muscles from 51 congenital muscular dystrophy (CMD) patients including 36 Fukuyama congenital muscular dystrophy (FCMD) and 15 non-FCMD (other CMD). 17 age-matched spinal muscular atrophy (SMA) and 5 Duchenne muscular dystrophy (DMD) patient biopsies were studied as controls. All 15 non-FCMD and SMA patients showed normal localization of dystrophin at the surface membrane of each muscle fiber which was undetectable in DMD. In contrast, 34 of 36 FCMD patients exhibited an unusual immunostaining pattern with occasional (17-43%; mean = 28) negative or abnormally immunoreacted (partially deficient, fluffy or intense) fibers for dystrophin. Dystrophin was absent in 2 of 36 patients having a clinical diagnosis of FCMD, and intragenic deletion of the DMD gene was detected in one. Spectrin, a membrane cytoskeletal protein related to dystrophin, also showed an increased number of abnormally immunostained fibers in FCMD (25%), but not so high in age-matched DMD (9%) or SMA patient muscle (0%). Thus, our results suggested the presence of intrinsic factor(s) that produce abnormality of the plasma membrane of FCMD muscle.

Adolescent↗
PubMed1994

Expression of myosin isoforms and of desmin, vimentin and titin in Tunisian Duchenne-like autosomal recessive muscular dystrophy.

Morphological, morphometrical, histoenzymological, immunocytochemical and biochemical analysis were performed on muscle biopsies taken from patients suffering from tunisian autosomal recessive Duchenne-like muscular dystrophy (TDLMD) selected both by Duchenne-like clinical criteria and by the presence of normal dystrophin. Data were compared to that obtained from DMD biopsies characterized by the absence of dystrophin. The distribution of myosin heavy chain isoforms, desmin, vimentin and titin were determined in type I and type II muscle fibers. The protein pattern appeared to be less affected in TDLMD than in DMD biopsies. The regenerating fibers were mainly but not exclusively type IIC; a noticeable percentage of both type I and type II fibers coexpressed fast and slow MHC isoforms in TDLMD. This percentage was lower than in DMD. The expression of embryonic, fetal, and fast/slow myosin isoforms in type IIC fibers in TDLMD and DMD suggest different fiber type transformations in these two diseases.

Adolescent↗
PubMed1987

Accumulation of CK-MM is impaired in innervated and contracting cultured muscle fibers of Duchenne muscular dystrophy patients.

No specific abnormalities have been reproducibly manifested in aneurally cultured muscle of Duchenne muscular dystrophy (DMD) patients. We now report that the accumulation of the muscle-"specific" isozyme of creatine kinase (CK-MM) was significantly and preferentially impaired in long-term innervated contracting muscle fibers cultured from 4 DMD patients (DMD-InnCMFs) compared to: i) their noninnervated sister-cultured muscle fibers, and ii) innervated contracting control cultured human muscle fibers (Control-InnCHMFs). Accumulation of other muscle-"specific" isozymes (MSIs), viz. glycogen phosphorylase, phosphoglycerate mutase, and lactic dehydrogenase, was not significantly impaired. We have not observed preferentially-impaired CK-MM accumulation in any Control-InnCHMFs from 22 patients (children and adults) with a variety of neuromuscular diseases. There was no apparent difference between DMD-InnCMFs and Control InnCHMFs regarding: acceptance of innervation; neuronally-driven, virtually continuous muscle-fiber contractions; characteristic myofiber organization by phase-contrast microscopy, and increased longevity of the innervated fibers.

Animals↗
PubMed1991

Differences in the duration of sedative and anxiolytic effects of desmethyldiazepam in two outbred Wistar strains.

Different sensitivities to benzodiazepines have been described for various strains of both rats and mice suggesting that variations in biological features of the animals are responsible for these differences. Since all reports concern inbred strains, we studied two outbred Wistar strains which are used routinely in several research disciplines. The pharmacodynamics of desmethyldiazepam (DMD), the main active metabolite of diazepam in man, were compared for male rats of the Riv:TOX strain (from the National Institute of Public Health and Environmental Protection) and the Crl:(WI)BR strain. The duration of sedative action of DMD after oral administration, as derived from suppression of the nocturnal locomotor activity, was longer in the Riv:TOX strain than in the Crl:(WI)BR strain. Accordingly, suppression of novelty-induced corticosterone release as an index of anxiolytic action was observed 11 hours after DMD administration in Riv:TOX rats but not in Crl:(WI)BR rats. At that time, serum DMD concentration was shown to be higher in the Riv:TOX strain than in the Crl:(WI)BR strain. The data are discussed in relation with possible metabolic differences between the two strains.

Animals↗
PubMed1988

Duchenne muscular dystrophy: deficiency of dystrophin at the muscle cell surface.

Dystrophin is the altered gene product in Duchenne muscular dystrophy (DMD). We used polyclonal antibodies against dystrophin to immunohistochemically localize the protein in human muscle. In normal individuals and in patients with myopathies other than DMD, dystrophin was localized to the sarcolemma of the fibers. The protein was absent or markedly deficient in DMD. The sarcolemmal localization of dystrophin is consistent with other evidence that there are structural and functional abnormalities of muscle surface membranes in DMD.

Cell Membrane↗
PubMed1990

Effect of dystrophin gene deletions on mRNA levels and processing in Duchenne and Becker muscular dystrophies.

Muscle dystrophin mRNAs from Duchenne (DMD) and Becker (BMD) patients with internal deletion of the DMD gene were quantitated and sequenced. In all cases (eight DMD and three BMD), truncated mature transcripts were found, and their amount was correlated to the clinical phenotype and to the reading frame. We focused on four cases that were apparently not in agreement with the reading frame rule. In two DMD cases, slightly reduced amounts of in-frame truncated mRNA are present but no dystrophin is detected, suggesting impaired translation and/or instability of the protein. In two BMD patients with out-of-frame deletions, the presence of minor in-frame alternatively spliced mRNA species is congruent with the observed truncated dystrophin and the mild phenotype.

Base Sequence↗
PubMed1990

Inhibition of spinal reflexes by paramedian reticular nucleus.

The inhibitory actions of the paramedian reticular nucleus (PRN), and its neighbouring structures, i.e., midline raphe nuclei (MRN) and dorsal medullary depressor area (DMD) on the knee jerk (KnJ) and crossed extension movement (CEM) induced by central sciatic stimulation and on the L5 ventral root response (EVRR) evoked by central tibial stimulation, were studied in cats under urethane (400 mg/kg) and alpha-chloralose (40 mg/kg) anesthesia alone, IP or further paralyzed with atracurium besylate (0.5 mg/kg/30 min), IV. Electrical stimulation of the above areas with rectangular pulses (80 Hz, 1.0 msec, 100-200 microA) decreased systemic arterial blood pressure (SAP) in an average value of: 36 +/- 3 mmHg for PRN; 19 +/- 2 mmHg for MRN; and 23 +/- 3 mmHg for DMD. The KnJ and CEM were almost completely suppressed by simultaneous PRN stimulation. The EVRR, including mono- and polysynaptic spinal reflexes with transmission velocity from 10 to 60 m/sec or above, were also suppressed. MRN stimulation only inhibited the KnJ, CEM and polysynaptic spinal reflexes with transmission velocities between 25 and 60 m/sec, but facilitated spinal reflexes with conduction velocities below 10 m/sec. On the other hand, DMD stimulation resulted in small suppression of KnJ, CEM and inhibition of polysynaptic spinal reflexes with conduction velocities between 25 and 60 m/sec. Even though MRN and DMD partially inhibited polysynaptic spinal reflexes, the magnitude of such inhibition was much smaller than that produced by PRN (-20% and -22% vs. -48%). The above-mentioned PRN effects on SAP and EVRR persisted in chronic animals decerebellated 9-12 days before.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Gene therapy in Duchenne muscular dystrophy.

Experiments in dystrophin gene transgenic mice have supported the concept of treating Duchenne muscular dystrophy (DMD) by demonstrating that regional expression of recombinant dystrophin in dystrophic muscle leads to regional restoration of normal muscle morphology and that dystrophin mini-genes driven by muscle specific regulatory elements are probably more effective than the full-length dystrophin gene. As a gene therapy trial for DMD, dystrophin cDNAs were introduced into skeletal muscle fibers of dystrophin-deficient mice (mdx) through direct DNA injection into plasmid expression vectors, and by replication-defective recombinant retrovirus or adenovirus vectors. With direct injection of dystrophin cDNA into a plasmid expression vector or retrovirus vectors, less than 10% of adult mdx fibers of the injected muscle expressed dystrophin. On the other hand, greater efficiency has been reported for recombinant adenovirus injection into young mdx muscle. However, it is necessary to develop vectors, viral or plasmid DNA, which can be injected intravenously and directed to muscle tissues. This will involve designing vectors possessing appropriate cell-type specific tropism and/or gene transcriptional activity for DMD treatment. This is anticipated to be a vital component in the second stage of experiments aimed at DMD treatment.

Animals↗
PubMedDate not supplied

Mosaic pattern of dystrophins in Duchenne muscular dystrophy.

Dystrophin is the gene product affected in Duchenne muscular dystrophy (DMD). Dystrophin is demonstrably absent with immunocytochemical staining and undetectable by western blotting of DMD muscles. We report an isolated 7-year-old girl with DMD. Analysis of the patient's and her mother's DNA, with probes covering the DMD gene, disclosed no deletion. We have studied dystrophin in biopsied muscle from the patient using antidystrophin antibody in combination with immunofluorescence. Random presence of normal and dystrophin-deficient fibers were indicative of mosaic expression. Dystrophin immunocytochemistry may be useful for accurate diagnosis of affected females.

Biopsy↗
PubMed1988

A deletion hot spot in the Duchenne muscular dystrophy gene.

We have made a detailed study of a deletion hot spot in the distal half of the Duchenne muscular dystrophy (DMD) gene, using intragenic probe P20 (DXS269), isolated by a hybrid cell-mediated cloning procedure. P20 detects 16% deletions in patients suffering from either DMD or Becker muscular dystrophy (BMD), in sharp contrast to the adjacent intragenic markers JBir (7%) and J66 (less than 1%), mapping respectively 200-320 kb proximal and 380-500 kb distal to P20. Of the P20 deletions, 30% start within a region of 25-40 kb, the majority extending distally. P20 was confirmed to map internal to a distal intron of the DMD gene. This region was recently shown by both cDNA analysis (M. Koenig et al., 1987; Cell 50: 509-517), and field inversion electrophoresis studies (J.T. Den Dunnen et al., 1987, Nature (London) 329: 640-642) to be specifically prone to deletions. In addition, P20 detects MspI and EcoRV RFLPs, informative in 48% of the carrier females. Together, these properties make P20 useful for carrier detection, prenatal diagnosis, and the study of deletion induction in both DMD and BMD.

Cell Line↗
PubMed1992

Mapping of FMR1, the gene implicated in fragile X-linked mental retardation, on the mouse X chromosome.

A genetic map of the Cf-9 to Dmd region of the mouse X chromosome has been established by typing 100 offspring from a Mus musculus x Mus spretus interspecific backcross for the four loci Cf-9, Cdr, Gabra3, and Dmd. The following order and genetic distances in centimorgans were determined: (Cf-9)-2.4 +/- 1.7-(Cdr)-2.0 +/- 1.4-(Gabra3)-4.1 +/- 2.0-(Dmd). Six backcross offspring carrying X chromosomes with recombination events in the Cdr-Dmd region were identified. These recombination events were used to define the position of Fmr-1, the murine homologue of FMR1, which is the gene implicated in the fragile X syndrome in man, and that of DXS296h, the murine homologue of DXS296. Both Fmr-1 and DXS296h were mapped into the same recombination interval as Gabra3 on the mouse X chromosome. These findings provide strong support for the concept that the order of loci lying in the Cf-9 to Gabra3 segment of the X chromosome is highly conserved between human and mouse.

Animals↗
PubMed1993

Deficiency of dystrophin-associated proteins: a common mechanism leading to muscle cell necrosis in severe childhood muscular dystrophies.

Dystrophin is a large cytoskeletal protein encoded by the Duchenne muscular dystrophy (DMD) gene. Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoproteins, including the novel laminin-binding glycoprotein called dystroglycan, which provides a linkage to the extracellular matrix. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins. In severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype (SCARMD), a specific deficiency of the 50 kDa dystrophin-associated glycoprotein is found. Thus, the disruption/dysfunction of the dystrophin-glycoprotein complex due to the deficiency of one or more of the dystrophin-associated proteins is presumed to cause the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. This may render muscle cells susceptible to necrosis in two forms of severe childhood muscular dystrophy, DMD and SCARMD.

Child↗
PubMed1993

Dystrophin-positive myotubes in innervated muscle cultures from Duchenne and Becker muscular dystrophy patients.

Nerve-muscle co-cultures from five Duchenne muscular dystrophy (DMD) patients and one Becker (BMD) patient, were studied by immunocytochemistry with antibodies against different portions of dystrophin. Four DMD patients had a deletion in the dystrophin gene. Some dystrophin-positive myotubes were detected in a few samples of all DMD cases. PCR amplification of exon 8 of the dystrophin gene ruled out a contamination from rat spinal cord during innervation. Our results in three DMD cases, may be explained by a clonal selection of dystrophin-positive fibers observed in muscle biopsies, while in the other two cases, a "frame-restoring" mutation might account for the presence of dystrophin-positive myotubes. The possible expression of "dystrophin-related protein" or dystrophin immature isoform was considered. In the BMD case an abnormal truncated dystrophin was found in innervated muscle cultures, as well as in muscle biopsy.

Adolescent↗
PubMedDate not supplied

The "rescue" of dystrophin synthesis in boys with Duchenne muscular dystrophy.

Over the last few years it has become clear that a proportion of biopsies from patients with Duchenne muscular dystrophy (DMD) contain fibres which show dystrophin-positive immunolabelling. We have collected evidence to demonstrate that low level restoration of the reading frame must have been taking place and that a BMD-like protein was being synthesized in DMD muscle. We have also found a relationship between the abundance of dystrophin (determined by densitometric analysis of blots) and the age at which boys lose the ability to walk independently. Thus, even the low levels of dystrophin in DMD patients may have a functional significance. We now suggest that exon skipping, whereby an existing frame-shifting deletion is modified and extended to an in-frame mutation, may be responsible for the limited rescue of dystrophin synthesis in the muscle from many DMD patients.

Adolescent↗
PubMed1994

Expression of dystrophin-associated proteins in dystrophin-positive muscle fibers (revertants) in Duchenne muscular dystrophy.

The dystrophin-glycoprotein complex spans the sarcolemma to provide a linkage between the subsarcolemmal cytoskeleton and the extracellular matrix in skeletal muscle. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins in the sarcolemma, thus causing the disruption of the dystrophin-glycoprotein complex and the loss of the linkage to the extracellular matrix. This is presumed to lead to sarcolemmal instability which could render muscle fibers susceptible to necrosis. In DMD, a very small percentage of muscle fibers show dystrophin staining along the sarcolemma, presumably due to a second in-frame deletion in the dystrophin gene. However, the functional significance of these rare dystrophin-positive muscle fibers (revertants) in DMD has been unclear. Here we report the co-expression of the dystrophin-associated proteins with dystrophin in revertants of DMD skeletal muscle. Our results suggest that the entire dystrophin-glycoprotein complex is restored in revertants and, thus, the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix is restored in these muscle fibers.

Cytoskeletal Proteins↗
PubMed1994

Cognitive impairment in Duchenne muscular dystrophy.

Cognitive function and dystrophin gene mutations were investigated in 50 DMD patients (mean age 11.1 yr; range 3.5-20.3). General intelligence assessment showed 31% of patients with Wechsler full intelligence quotient (FIQ) lower than 75 (normal values: 100 +/- 14), and only 24% with appropriate FIQ level. Modal distribution of Wechsler verbal, performance, and FIQs, and Raven IQs was normal. Verbal IQ was more affected than performance IQ (PIQ) only in the younger group of subjects. Low PIQ correlated with the presence of macroglossia, detected in 13 out of 50 patients. Impairment of productive language was of non-dysphasic nature and correlated with defects of short-term memory, which was also affected in non-verbal skills. DMD patients shared the same spectrum of neuropsychological defects, regardless of whether they were or were not mentally retarded. The proportion of patients with dystrophin gene deletions was 64%. No statistically significant correlations were found between genetic data and psychometric assessment. Finally, (18F)-fluorodeoxyglucose positron emission tomography studies demonstrated cerebellar hypometabolism in all the DMD patients examined and variable involvement of associative cortical areas. These findings suggest a possible role of the cerebral and cerebellar hypometabolism in the cognitive impairment of DMD.

Adolescent↗