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)

alpha-Sarcoglycan is a 50 kDa single-pass transmembrane glycoprotein exclusively expressed in striated muscle that, together with beta-, gamma-, and delta-sarcoglycan, forms a sub-complex at the muscle fibre cell membrane. The sarcoglycans are components of the dystrophin-associated glycoprotein (DAG) complex which forms a mechanical link between the intracellular cytoskeleton and extracellular matrix. The DAG complex function is to protect the muscle membrane from the stress of contractile activity and as a structure for the docking of signalling proteins. Genetic defects of DAG components cause muscular dystrophies. A lack or defects of alpha-sarcoglycan causes the severe type 2D limb girdle muscular dystrophy. alpha-Sarcoglycan-null (Sgca-null) mice develop progressive muscular dystrophy similar to the human disorder. This animal model was used in the present work for an ultrastructural study of diaphragm muscle. Diaphragm from Sgca-null mouse presents a clear dystrophic phenotype, with necrosis, regeneration, fibre hypertrophy and splitting, excess of collagen and fatty infiltration. Some abnormalities were also observed, such as centrally located nuclei of abnormal shape, fibres containing inclusion bodies within the contractile structure, and fibres with electron-dense material dispersed over almost the entire cell. Additionally, unusual interstitial cells of uncertain identity were detected within muscle fibres. The abnormal ultrastructure of the diaphragm from Sgca-null mice is discussed.
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PMID:Ultrastructure of diaphragm from dystrophic alpha-sarcoglycan-null mice. 1599 Sep 25

NG2, the rat homologue of the human melanoma chondroitin sulfate proteoglycan (MCSP), is a ligand for collagen VI (COL6). We have examined skeletal muscles of patients affected by Ullrich scleroatonic muscular dystrophy (UCMD), an inherited syndrome caused by COL6 genes mutations. A significant decrease of NG2 immunolabeling was found in UCMD myofibers, as well as in skeletal muscle and cornea of COL6 null-mice. In UCMD muscles, truncated NG2 core protein isoforms were detected. However, real-time RT-PCR analysis revealed marked increase in NG2 mRNA content in UCMD muscle compared to controls. We hypothesize that NG2 immunohistochemical and biochemical behavior may be compromised owing to the absence of its physiological ligand. MCSP/NG2 proteoglycan may be considered an important receptor mediating COL6-sarcolemma interactions, a relationship that is disrupted by the pathogenesis of UCMD muscle.
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PMID:Altered expression of the MCSP/NG2 chondroitin sulfate proteoglycan in collagen VI deficiency. 1616 45

Biglycan and decorin are small extracellular proteoglycans that interact with cytokines, whose activity they may modulate, and with matrix proteins, particularly collagens. To better understand their role in muscle fibrosis, we investigated expression of decorin and biglycan transcripts and protein in muscle of several forms of muscular dystrophy, and also expression of perlecan, an extracellular proteoglycan unrelated to collagen deposition. In Duchenne muscular dystrophy (DMD) and LAMA2-mutated congenital muscular dystrophy (MDC1A) we also quantitated transcript levels of the profibrotic cytokine TGF-beta1. We examined muscle biopsies from nine DMD patients, aged 2-8 years; 14 BMD (Becker muscular dystrophy) patients (nine aged 1-5 years; five aged 30-37 years); four MDC1A patients (aged 2-7 years); six dysferlin-deficient patients (aged 19-53 years) with mutation ascertained in two, and normal expression of proteins related to limb girdle muscular dystrophies in the others; 10 sarcoglycan-deficient patients: seven with alpha-sarcoglycan mutation, two with beta-sarcoglycan mutation and one with gamma-sarcoglycan mutation (five aged 8-15 years; five aged 26-43 years); and nine children (aged 1-6 years) and 12 adults (aged 16-61 years) suspected of neuromuscular disease, but who had normal muscle on biopsy. Biglycan mRNA levels varied in DMD and MDC1A depending on the quantitation method, but were upregulated in BMD, sarcoglycanopathies and dysferlinopathy. Decorin mRNA was significantly downregulated in DMD and MDC1A, whereas TGF-beta1 was significantly upregulated. Decorin mRNA was normal in paediatric BMD, but upregulated in adult BMD, sarcoglycanopathies and dysferlinopathy. Perlecan transcript levels were similar to those of age-matched controls in all disease groups. By immunohistochemistry, decorin and biglycan were mainly localized in muscle connective tissue; their presence increased in relation to increased fibrosis in all dystrophic muscle. By visual inspection, decorin bands on immunoblot did not differ from those of age-matched controls in all patient groups. However, when the intensity of the bands was quantitated against vimentin and normalized against sarcomeric actin, in DMD and MDC1A the ratio of band intensities was significantly lower than in age-matched controls. Variations in the transcript and protein levels of these proteoglycans in different muscular dystrophies probably reflect the variable disruption of extracellular matrix organization that occurs in these diseases. The significantly lowered decorin levels in DMD and MDC1A may be related to the increased TGF-beta1 levels, suggesting a therapeutic role of decorin in these severe dystrophies.
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PMID:Decorin and biglycan expression is differentially altered in several muscular dystrophies. 1618 58

Fibrosis is a common pathological feature observed in muscle from patients with Duchenne muscular dystrophy and in mdx diaphragm. The purpose of this study was to determine whether pentoxifylline (PTX) treatment for 4 weeks (16 mg/kg/day) could significantly attenuate the process of fibrosis in diaphragm muscle from mdx mice. PTX treatment had no impact on in vitro diaphragm muscle contractile function. In addition, diaphragm muscle hydroxyproline concentration and the level of type I and III collagen and TGF-beta1 mRNA were unaffected by PTX treatment. These findings do not support the use of PTX as an antifibrotic drug for the treatment of muscular dystrophy.
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PMID:Pentoxifylline fails to attenuate fibrosis in dystrophic (mdx) diaphragm muscle. 1650 23

Although genetic mutations that are responsible for most of the inherited neuromuscular diseases have been identified, the molecular and cellular mechanisms that cause muscle and nerve depletion are not well understood and therapies are lacking. Histological studies of many neuromuscular diseases indicated that loss of motor-nerve and/or skeletal-muscle function might be due to excessive cell death by apoptosis. Recent studies have confirmed this possibility by showing that pathology in mouse models of amyotrophic lateral sclerosis, congenital muscular dystrophy, oculopharyngeal muscular dystrophy and collagen-VI deficiency, but not Duchenne muscular dystrophy, is significantly ameliorated by genetic or pharmacological interventions that have been designed to inhibit apoptosis. Thus, apoptosis greatly contributes to pathology in mouse models of several neuromuscular diseases, and appropriate anti-apoptosis therapy might therefore be beneficial for the corresponding human diseases.
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PMID:The role of apoptosis in neuromuscular diseases and prospects for anti-apoptosis therapy. 1665 Aug 5

Congenital muscular dystrophies (CMDS) are a heterogeneous group of disorders. A growing number of CMDS have been found to be associated with joint hyperlaxity. We recruited 14 French-Canadian cases belonging to 11 families affected by a novel autosomal recessive congenital muscular dystrophy with hyperlaxity (CMDH). All cases come from the southwestern part of Quebec, suggesting a new French-Canadian founder effect. All patients present muscle weakness, proximal contractures coexisting with distal joint hyperlaxity. Pathological and genetic studies have excluded that mutations in the three genes coding for collagen VI subunits are responsible for this disease. A genome-wide scan established linkage of two CMDH families to a region on chromosome 3p23-21. Further linkage analysis confirmed that all families are linked to the same region (log of the odds score of 5.3). Haplotype analysis defines a 1.6-cM candidate interval and suggests that two common mutations may account for 78% of carrier chromosomes. This study describes and maps a new form of recessive CMD with joint hyperlaxity distinct from Ullrich and Bethlem myopathies with a founder effect in the French-Canadian population.
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PMID:A new form of congenital muscular dystrophy with joint hyperlaxity maps to 3p23-21. 1676 Jan 98

Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that degrades aberrant mRNAs containing premature translation termination codons (PTCs). The essential proteins for NMD include SMG-1, a protein kinase, and Upf1, a substrate of SMG-1 with RNA helicase activity. In this study, we evaluated the effects of NMD inhibition by siRNA-mediated knockdown of SMG-1 or Upf1 on the phenotype of Ullrich disease, an autosomal recessive congenital muscular dystrophy. The patient studied showed a homozygous frameshift mutation with a PTC in the collagen VI alpha2 gene, which encodes a truncated but partially functional protein. The patient's fibroblasts showed a nearly complete loss of the triple-helical collagen VI protein and functional defects in the extracellular matrix (ECM) due to the crucial deficiency of the collagen VI alpha2 protein. We have shown that siRNA-mediated knockdown of SMG-1 or Upf1 causes the up-regulation of the mutant triple-helical collagen VI, resulting in the formation of partially functional ECM. We suggest that the inhibition of NMD may be useful as a therapeutic approach to treat some human genetic diseases exacerbated by NMD.
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PMID:Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts. 1680 16

Biglycan is an extracellular ligand for the dystrophin-associated protein complex (DAPC) that is upregulated in both dystrophic and regenerating muscle. Biglycan also binds to collagen VI, mutations of which cause a congenital muscular dystrophy (Ullrich's; UCMD) that is also characterized by connective tissue abnormalities. The expression of biglycan in early development and postnatal ages has not been well characterized. Here we show that biglycan transcript levels peak at approximately 21 weeks' gestation in human fetal muscle. Immunocytochemical analysis of developing mouse muscle shows that biglycan can be detected in muscle as early as embryonic day (E)16 and is most abundant between postnatal day (P)1 and P7. Biglycan is also highly expressed in developing tendon, with maximal levels observed at E16-18. This robust tendon expression is correlated with a sharp peak in biglycan transcript levels in the hindlimb. Finally, at E18 collagen VI colocalizes with biglycan in tendon. These results suggest that biglycan has a particularly important function during muscle and connective tissue development. Moreover, biglycan may play a role in the pathogenesis of collagen VI-associated congenital muscular dystrophies.
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PMID:Developmental regulation of biglycan expression in muscle and tendon. 1681 Jun 81

Muscular dystrophies are a heterogeneous group of genetic disorders. In addition to genetic information, a combination of various approaches such as the use of genetic animal models, muscle cell biology, and biochemistry has contributed to improving the understanding of the molecular basis of muscular dystrophy's etiology. Several lines of evidence confirm that the structural linkage between the muscle extracellular matrix and the cytoskeleton is crucial to prevent the progression of muscular dystrophy. The dystrophin-glycoprotein complex links the extracellular matrix to the cytoskeleton, and mutations in the component of this complex cause Duchenne-type or limb-girdle-type muscular dystrophy. Mutations in laminin or collagen VI, muscle matrix proteins, are known to cause a congenital type of muscular dystrophy. Moreover, it is not only the primary genetic defects in the structural or matrix proteins, but also the primary mutations of enzymes involved in the protein glycosylation pathway that are now recognized to disrupt the matrix-cell interaction in a certain group of muscular dystrophies. This group of diseases is caused by the secondary functional defects of dystroglycan, a transmembrane matrix receptor. This review considers recent advances in understanding the molecular pathogenesis of muscular dystrophies that can be caused by the disruption of the cell-matrix linkage.
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PMID:The genetic and molecular basis of muscular dystrophy: roles of cell-matrix linkage in the pathogenesis. 1696 82

During the past decade, considerable progress in the field of congenital muscular dystrophies (CMDs) had led to the identification of a growing number of causative genes. This genetic progress has uncovered crucial pathophysiological concepts and has been instrumental in redefining clinical phenotypes. Important new pathogenic mechanisms include the disorders of O-mannosyl-linked glycosylation of alpha-dystroglycan as well as the involvement of a collagen type VI in the pathogenesis of congenital disorders of muscle. Thus, an emerging theme among gene products involved in the pathogenesis of congenital muscular dystrophy is their intimate connection to the extracellular matrix. In this review, we focus on the clinical phenotypes that we are correlating with the novel genetic and biochemical findings encountered within CMD. This correlation will frequently lead to a considerably expanded clinical spectrum associated with a given CMD gene.
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PMID:Congenital muscular dystrophies and the extracellular matrix. 1702 57


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