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

Dystroglycans are essential transmembrane adhesion receptors for laminin. Alpha-dystroglycan is a highly glycosylated extracellular protein that interacts with laminin in the extracellular matrix and the transmembrane region of beta-dystroglycan. Beta-dystroglycan, via its cytoplasmic tail, interacts with dystrophin and utrophin and also with the actin cytoskeleton. As a part of the dystrophin-glycoprotein complex of muscles, dystroglycan is also important in maintaining sarcolemmal integrity. Mutations in dystrophin that lead to Duchenne muscular dystrophy also lead to a loss of dystroglycan from the sarcolemma, and chimaeric mice lacking muscle dystroglycan exhibit a severe muscular dystrophy phenotype. Using yeast two-hybrid analysis and biochemical and cell biological studies, we show, in the present study, that the cytoplasmic tail of beta-dystroglycan interacts directly with F-actin and, furthermore, that it bundles actin filaments and induces an aberrant actin phenotype when overexpressed in cells.
 ...
PMID:Direct interaction of beta-dystroglycan with F-actin. 1289 61

Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. Through positional cloning, we identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein O-linked mannose beta1, 2-N-acetylglucosaminy ltransferase (POMGnT1), respectively. Recent studies have revealed that posttranslational modification of alpha-dystroglycan is associated with these congenital muscular dystrophies with brain malformations. In this review Fukuyama-type congenital muscular dystrophy (FCMD), other CMDs with brain malformations, and their relation with alpha-dystroglycan are discussed.
 ...
PMID:Fukuyama-type congenital muscular dystrophy (FCMD) and alpha-dystroglycanopathy. 1289 68

Sarcoglycans are transmembrane proteins important in the maintenance of proper muscle function. Together, the sarcoglycans form a heteromeric complex that interacts with dystrophin, dystroglycan, and filamin C to form a mechanosignaling complex. Mutations in the genes encoding sarcoglycan can produce cardiomyopathy and muscular dystrophy. Studies of patients and animal models have emphasized the variability in penetrance and severity of cardiomyopathy. In animal models of sarcoglycan mutations, muscular dystrophy develops owing to loss of the sarcoglycan complex at the membrane of skeletal myocytes. Cardiomyopathy similarly develops with evidence of focal areas of degeneration and necrosis, as well as loss of sarcoglycan at the cardiomyocyte membrane. Vascular spasm has been noted as a feature of sarcoglycan-mediated cardiomyopathy. Recent evidence suggests that disruption of the smooth muscle sarcoglycan complex is not required for the development of vascular spasm and that vascular spasm arises from a vascular smooth muscle cell-extrinsic process.
 ...
PMID:Sarcoglycans in vascular smooth and striated muscle. 1292 20

Recently, post-translational modification of proteins has been defined as a new area of focus for muscular dystrophy research by the identification of a group of disease genes that encode known or putative glycosylation enzymes. Walker-Warburg Syndrome (WWS) and muscle-eye-brain disease (MEB) are caused by mutations in two genes involved in O-mannosylation, POMT1 and POMGnT1, respectively. Fukuyama muscular dystrophy (FCMD) is due to mutations in fukutin, a putative phospholigand transferase. Congenital muscular dystrophy type 1C and limb girdle muscular dystrophy type 2I are allelic, both being due to mutations in the gene-encoding fukutin-related protein (FKRP). Finally, the causative gene in the myodystrophy (myd) mouse is a putative bifunctional glycosyltransferase (Large). WWS, MEB, FCMD and the myd mouse are also associated with neuronal migration abnormalities (often type II lissencephaly) and ocular or retinal defects. A deficiency in post-translational modification of alpha-dystroglycan is a common feature of all these muscular dystrophies and is thought to involve O-glycosylation pathways. This abnormally modified alpha-dystroglycan is deficient in binding to extracellular matrix ligands, including laminin and agrin. Selective deletion of dystroglycan in the central nervous system (CNS) produces brain abnormalities with striking similarities to WWS, MEB, FCMD and the myd mouse. Thus, impaired dystroglycan function is strongly implicated in these diseases. However, it is unlikely that these five glycosylation enzymes only have a role in glycosylation of alpha-dystroglycan and it is important that other protein targets are identified.
 ...
PMID:Glycosylation defects: a new mechanism for muscular dystrophy? 1292 72

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of alpha-dystroglycan. Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, each associated with eye abnormalities and neuronal migration defects, result from mutations in fukutin, POMGnT1 and POMT1, respectively, while mutations in the fukutin-related protein (FKRP) gene cause congenital muscular dystrophy 1C, typically lacking brain involvement. Another putative glycosyltransferase, Large, is mutated in the myodystrophy mouse. The human homologue of this gene is therefore a strong candidate for involvement in novel forms of muscular dystrophy. We studied 36 patients with muscular dystrophy and either mental retardation, structural brain changes or abnormal alpha-dystroglycan immunolabelling, unlinked to any reported CMD loci. Linkage analysis in seven informative families excluded involvement of LARGE but sequencing of this gene in the remaining 29 families identified one patient with a G1525A (Glu509Lys) missense mutation and a 1 bp insertion, 1999insT. This 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabelling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of alpha-dystroglycan that retained some laminin binding activity. This is the first description of mutations in the human LARGE gene and we propose to name this new disorder MDC1D.
 ...
PMID:Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. 1296 29

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is absent in the skeletal muscle of DMD patients and mdx mice. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers, and are thought to undergo degradation through an unknown pathway. As such, we reasoned that inhibition of the proteasomal degradation pathway might rescue the expression and subcellular localization of dystrophin-associated proteins. To test this hypothesis, we treated mdx mice with the well-characterized proteasomal inhibitor MG-132. First, we locally injected MG-132 into the gastrocnemius muscle, and observed the outcome after 24 hours. Next, we performed systemic treatment using an osmotic pump that allowed us to deliver different concentrations of the proteasomal inhibitor, over an 8-day period. By immunofluorescence and Western blot analysis, we show that administration of the proteasomal inhibitor MG-132 effectively rescues the expression levels and plasma membrane localization of dystrophin, beta-dystroglycan, alpha-dystroglycan, and alpha-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore, we show that systemic treatment with the proteasomal inhibitor 1) reduces muscle membrane damage, as revealed by vital staining (with Evans blue dye) of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and 2) ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice. Thus, the current study opens new and important avenues in our understanding of the pathogenesis of DMD. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.
 ...
PMID:Proteasome inhibitor (MG-132) treatment of mdx mice rescues the expression and membrane localization of dystrophin and dystrophin-associated proteins. 1450 73

Most proteins within living organisms contain glycans. Glycan structures can modulate the biological properties and function of glycoproteins. Developments in glycobiology have revealed a new type of glycosidic linkage to the peptide portion, the O-mannosyl linkage in mammals, although heretofore it had been thought to be specific to yeast. One of the best known O-mannosyl-modified glycoproteins is dystroglycan, which is a central component of dystrophinglycoprotein complex isolated from skeletal muscle membranes. We identify and characterize a glycosyltransferase, UDP-N-acetylglucosamine: protein O-mannose beta 1,2-N-acetylglucosaminyltransferase (POMGnT1), involved in the biosynthesis of mammalian type O-mannosyl glycans. Finally, we find that the POMGnT1 gene is responsible for muscle-eye-brain disease (MEB). MEB is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities and brain malformation (type II lissencephaly). Like MEB, recent data suggest that the aberrant protein glycosylation of a specific glycoprotein, alpha-dystroglycan, is the primary cause of some forms of congenital muscular dystrophy. Here I review the new insight into glycobiology of muscular dystrophy and neuronal migration disorder.
 ...
PMID:[Finding of O-mannosyl glycan in mammals and congenital muscular dystrophies due to glycosylation defects]. 1457 28

Mammalian cells produce many glycoproteins, i.e., proteins with covalently attached sugar chains. Recent advances in glycobiology have revealed the importance of sugar chains as biosignals for multi-cellular organisms including cell-cell communication, intracellular signaling, protein folding, and targeting of proteins within cells. The O-mannosyl linkage, which used to be considered specific to yeast, has recently been found in mammals. One of the best known O-mannosyl-modified glycoproteins is alpha-dystroglycan, which is a central component of the dystrophin-glycoprotein complex isolated from skeletal muscle membranes. We have identified and characterized a glycosyltransferase, UDP-N-acetylglucosamine: protein O-mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1), involved in the biosynthesis of O-mannosyl glycans. We subsequently found that loss of function of the POMGnT1 gene is responsible for muscle-eye-brain disease (MEB). MEB is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities and brain malformation (type II lissencephaly). Moreover, recent data suggest that aberrant protein glycosylation of alpha-dystroglycan is the primary cause of some forms of congenital muscular dystrophy. Here we review new insights into the glycobiology of muscular dystrophy and neuronal migration disorder.
 ...
PMID:Glycosylation in congenital muscular dystrophies. 1464 63

The congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies. Patients show congenital hypotonia, muscle weakness, and dystrophic changes on muscle biopsy. Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of alpha-dystroglycan on muscle biopsy. FKRP mutations account for a broad spectrum of patients with muscular dystrophy, from a severe congenital form with or without mental retardation (MDC1C) to a much milder limb-girdle muscular dystrophy (LGMD2I). We identified two novel homozygous missense FKRP mutations, one, A455D, in six unrelated Tunisian patients and the other, V405L, in an Algerian boy. The patients, between the ages of 3 and 12 years, presented with a severe form of MDC1C with calf hypertrophy and high serum creatine kinase levels. None had ever walked. Two had cardiac dysfunction and one strabismus. They all had mental retardation, microcephaly, cerebellar cysts, and hypoplasia of the vermis. White matter abnormalities were found in five, mostly when cranial magnetic resonance imaging was performed at a young age. These abnormalities were shown to regress in one patient, as has been observed in patients with Fukuyama CMD. Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation. These results strongly suggest that particular FKRP mutations in the homozygous state induce structural and clinical neurological lesions in addition to muscular dystrophy. They also relate MDC1C to other CMD with abnormal protein glycosylation and disordered brain function.
 ...
PMID:New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. 1465 96

The limb girdle muscular dystrophies are a heterogeneous group of conditions characterized by proximal muscle weakness and disease onset ranging from infancy to adulthood. We report here eight patients from seven unrelated families affected by a novel and relatively mild form of autosomal recessive limb girdle muscular dystrophy (LGMD2) with onset in the first decade of life and characterized by severe mental retardation but normal brain imaging. Immunocytochemical studies revealed a significant selective reduction of alpha-dystroglycan expression in the muscle biopsies. Linkage analysis excluded known loci for both limb girdle muscular dystrophy and congenital muscular dystrophies in the consanguineous families. We consider that this represents a novel form of muscular dystrophy with associated brain involvement. The biochemical studies suggest that it may belong to the growing number of muscular dystrophies with abnormal expression of alpha-dystroglycan.
 ...
PMID:A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan. 1467 99


<< Previous 1 2 3 4 5 6 7 8 9 10