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)

Walker-Warburg syndrome (WWS) is the most severe of a group of congenital disorders that have in common defects in the O-glycosylation of alpha-dystroglycan. WWS is characterized by congenital muscular dystrophy coupled with severe ocular and brain malformations. Moreover, in at least one-fifth of the reported cases, mutations in the POMT1 gene are responsible for this disease. During embryonic development (E8.5 to E11.5), the mouse Pomt1 gene is expressed in the tissues most severely affected in WWS, the muscle, eye, and brain. In this study, we show that mPomt1 expression is maintained in the muscle and eye in later developmental stages and, notably, that its expression is particularly strong in regions of brain and cerebellum that, when affected, could generate the defects observed in patients with WWS. We show that the Pomt1 protein is localized to the sarcoplasmic reticulum of muscle tissue cells in adult mice, where alpha-dystroglycan is O-glycosylated. Furthermore, the Pomt1 protein is localized to the acrosome of maturing spermatids, where alpha-dystroglycan is not glycosylated, so that Pomt1 might have a different target for O-mannosylation in the testes. This expression pattern in the testes could also be related to the gonadal anomalies observed in some patients with WWS.
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PMID:Expression of the murine Pomt1 gene in both the developing brain and adult muscle tissues and its relationship with clinical aspects of Walker-Warburg syndrome. 1745 71

Examination of embryonic myogenesis of two distinct, but functionally related, skeletal muscle dystrophy mutants (mdx and cav-3(-/-)) establishes for the first time that key elements of the pathology of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy type 1C (LGMD-1c) originate in the disruption of the embryonic cardiac and skeletal muscle patterning processes. Disruption of myogenesis occurs earlier in mdx mutants, which lack a functional form of dystrophin, than in cav-3(-/-) mutants, which lack the Cav3 gene that encodes the protein caveolin-3; this finding is consistent with the milder phenotype of LGMD-1c, a condition caused by mutations in Cav3, and the earlier [embryonic day (E)9.5] expression of dystrophin. Myogenesis is severely disrupted in mdx embryos, which display developmental delays; myotube morphology and displacement defects; and aberrant stem cell behaviour. In addition, the caveolin-3 protein is elevated in mdx embryos. Both cav-3(-/-) and mdx mutants (from E15.5 and E11.5, respectively) exhibit hyperproliferation and apoptosis of Myf5-positive embryonic myoblasts; attrition of Pax7-positive myoblasts in situ; and depletion of total Pax7 protein in late gestation. Furthermore, both cav-3(-/-) and mdx mutants have cardiac defects. In cav-3(-/-) mutants, there is a more restricted phenotype comprising hypaxial muscle defects, an excess of malformed hypertrophic myotubes, a twofold increase in myonuclei, and reduced fast myosin heavy chain (FMyHC) content. Several mdx mutant embryo pathologies, including myotube hypotrophy, reduced myotube numbers and increased FMyHC, have reciprocity with cav-3(-/-) mutants. In double mutant (mdxcav-3(+/-)) embryos that are deficient in dystrophin (mdx) and heterozygous for caveolin-3 (cav-3(+/-)), whereby caveolin-3 is reduced to 50% of wild-type (WT) levels, these phenotypes are severely exacerbated: intercostal muscle fibre density is reduced by 71%, and Pax7-positive cells are depleted entirely from the lower limbs and severely attenuated elsewhere; these data suggest a compensatory rather than a contributory role for the elevated caveolin-3 levels that are found in mdx embryos. These data establish a key role for dystrophin in early muscle formation and demonstrate that caveolin-3 and dystrophin are essential for correct fibre-type specification and emergent stem cell function. These data plug a significant gap in the natural history of muscular dystrophy and will be invaluable in establishing an earlier diagnosis for DMD/LGMD and in designing earlier treatment protocols, leading to better clinical outcome for these patients.
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PMID:Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation. 1953 99