Disease relevance of Muscular Dystrophies

• Indeed, studies in caveolin-deficient mice have implicated these structures in a host of human diseases, including diabetes, cancer, cardiovascular disease, atherosclerosis, pulmonary fibrosis, and a variety of degenerative muscular dystrophies [1].
• Duchene muscular dystrophy (DMD) is a fatal progressive X-linked muscle disorder, caused by mutations in the dystrophin gene [2].
• Myotonic dystrophy (DM) is a multi-system disease and the most common form of muscular dystrophy in adults [3].
• Plectin deficiency results in muscular dystrophy with epidermolysis bullosa [4].
• Histopathological analysis of the mutant mice revealed several abnormalities, including dilated cardiomyopathy, muscular dystrophy and lipodystrophy [5].

Psychiatry related information on Muscular Dystrophies

• Expansion of (AGC)n repeats has been associated with genetic disorders called triplet-repeat diseases such as Huntington's disease (HD), myotonic muscular dystrophy (DM) and Kennedy's disease [6].
• Two siblings with a congenital muscular dystrophy and severe mental retardation which was not due to dystrophin, merosin, or adhalin deficiency are described [7].

High impact information on Muscular Dystrophies

• Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function [8].
• Reduced ligand binding activity of alpha-dystroglycan is associated with muscle and central nervous system pathogenesis in a growing number of muscular dystrophies [9].
• We demonstrate a similar phenomenon of reexpression of functional dystroglycan in regenerating muscle fibers in a mild form of human muscular dystrophy caused by disruption of posttranslational dystroglycan processing [10].
• Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome [11].
• Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A) [12].

Chemical compound and disease context of Muscular Dystrophies

• Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy [13].
• Allopurinol in Duchenne's muscular dystrophy [14].
• Therefore, the loss of this glycoprotein is a common denominator of the pathological process leading to muscle cell necrosis in two forms of muscular dystrophy, DMD and SCARMD [15].
• Postponement of symptoms of hereditary muscular dystrophy in chickens by 5-hydroxytryptamine antagonists [16].
• Gene transfer of LARGE into the cells of individuals with congenital muscular dystrophies restores alpha-DG receptor function, whereby glycan-enriched alpha-DG coordinates the organization of laminin on the cell surface [17].

Biological context of Muscular Dystrophies

• Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse [18].
• Analysis of dystrophin expression after activation of myogenesis in amniocytes, chorionic-villus cells, and fibroblasts. A new method for diagnosing Duchenne's muscular dystrophy [19].
• We have found a 2 kilobase insertion containing a rearranged L1 element in the dystrophin gene of a muscular dystrophy patient [20].
• We have investigated the possibility that a deficiency of a dystrophin-associated protein could be the cause of severe childhood autosomal recessive muscular dystrophy (SCARMD) with a DMD-like phenotype [15].
• alpha-Dystroglycan (alpha-DG) is a component of the dystroglycan complex, which is involved in early development and morphogenesis and in the pathogenesis of muscular dystrophies [21].

Anatomical context of Muscular Dystrophies

• Here we report that chimaeric mice generated with ES cells targeted for both Dg alleles have skeletal muscles essentially devoid of Dgs and develop a progressive muscle pathology with changes emblematic of muscular dystrophies in humans [22].
• The cause of the pathological and functional abnormalities we describe in smooth muscle is unknown but may be a deficiency of dystrophin, the recently identified gene product of the Duchenne's muscular dystrophy locus [23].
• We show here for the first time that muscle membranes of patients with myotonic muscular dystrophy contain the receptor for apamin, a bee venom toxin known to be a specific and high-affinity blocker of one class of Ca2+-activated K+ channels in mammalian muscle [24].
• FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies [25].
• The study demonstrates that wild-type bone marrow-derived side population stem cells are indeed readily incorporated into both skeletal and cardiac muscle when transplanted into mice that lack delta-sarcoglycan -- a model of cardiomyopathy and muscular dystrophy [26].

Gene context of Muscular Dystrophies

• Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain [27].
• Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene [28].
• Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy [29].
• Beta-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex [30].
• Expression of full-length utrophin prevents muscular dystrophy in mdx mice [31].

Analytical, diagnostic and therapeutic context of Muscular Dystrophies

• Serum antibodies to the deleted dystrophin sequence after cardiac transplantation in a patient with Becker's muscular dystrophy [32].
• As these cells can be isolated from the blood, manipulated in vitro, and delivered through the circulation, they represent a possible tool for future cell therapy applications in DMD disease or other muscular dystrophies [33].
• There are a few naturally occurring animal models of DGC-associated muscular dystrophy (e.g. the dystrophin-deficient mdx mouse, dystrophic golden retriever dog, HFMD cat and the delta-sarcoglycan-deficient BIO 14.6 cardiomyopathic hamster) that share common genetic protein abnormalities similar to those of the human disease [34].
• The majority of mutations in Xp21-linked muscular dystrophy (MD) can be identified by PCR or Southern blotting, as deletions or duplications of groups of exons in the dystrophin gene, but it is not always possible to predict how much altered dystrophin, if any, will be produced [35].
• Our results show that functional abnormalities of dystrophic muscle can be corrected by delivery of full-length dystrophin to adult, immunocompetent mdx mice, raising the prospects for gene therapy of muscular dystrophies [36].

References