Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal recessive limb-girdle muscular dystrophies represent a genetically heterogeneous group of diseases characterized by a progressive involvement of skeletal muscles. They show a wide spectrum of clinical courses, varying from very mild to severe. Eight loci responsible for autosomal recessive limb-girdle muscular dystrophies have been mapped and six defective genes identified. In this study, we report the clinical data, muscle biopsy findings and results of genetic linkage analysis in a large consanguineous Tunisian family with 13 individuals suffering from autosomal recessive limb-girdle muscular dystrophy. Clinical features include variable age of onset, proximal limb muscle weakness and wasting predominantly affecting the pelvic girdle, and variable course between siblings. CK rate was usually high in younger patients. Muscle biopsy showed dystrophic changes with normal expression of dystrophin and various proteins of the dystrophin-associated protein complex (sarcoglycan sub-units, dystroglycan, and sarcospan). Genetic linkage analysis excluded the known limb-girdle muscular dystrophies loci as well as ten additional candidate genes. A maximum LOD score of 4.36 at θ=0.00 was obtained with marker D19S606, mapping this new form of autosomal recessive limb-girdle muscular dystrophy to chromosome 19q13.3.
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PMID:A new locus for autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3. 1083 49

Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal muscle weakness and often cardiomyopathy and are due to mutations in the genes encoding beta- and delta-sarcoglycan. We previously demonstrated that loss of sarcoglycans in smooth muscle leads to constrictions of the microvasculature that contributes to the cardiac phenotype. It is unclear how vasculature abnormalities affect skeletal muscle. We injected recombinant beta- or delta-sarcoglycan adenoviruses into skeletal muscles of corresponding null mice. We hypothesized that the adenoviruses would not transduce vascular smooth muscle, and we would only target skeletal muscle. Indeed, sustained expression of intact sarcoglycan-sarcospan complex was noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in peripheral nerve, but not in vascular smooth muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathological dystrophy and hypertrophy, and protected against exercised-induced damage. We conclude that vascular dysfunction is not a primary cause of beta- and delta-sarcoglycan-deficient muscular dystrophy. In addition, we show successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of sarcoglycans to skeletal muscle in combination with pharmacological prevention of cardiomyopathy constitute promising therapeutic strategies for limb-girdle muscular dystrophies.
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PMID:Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy. 1285 63

Duchenne/Becker and limb-girdle muscular dystrophies share clinical symptoms like muscle weakness and wasting but differ in clinical presentation and severity. To get a closer view on the differentiating molecular events responsible for the muscular dystrophies, we have carried out a comparative gene expression profiling of hindlimb muscles of the following mouse models: dystrophin-deficient (mdx, mdx(3cv)), sarcoglycan-deficient (Sgca null, Sgcb null, Sgcg null, Sgcd null), dysferlin-deficient (Dysf null, SJL(Dysf)), sarcospan-deficient (Sspn null), and wild-type (C57Bl/6, C57Bl/10) mice. The expression profiles clearly discriminated between severely affected (dystrophinopathies and sarcoglycanopathies) and mildly or nonaffected models (dysferlinopathies, sarcospan-deficiency, wild-type). Dystrophin-deficient and sarcoglycan-deficient profiles were remarkably similar, sharing inflammatory and structural remodeling processes. These processes were also ongoing in dysferlin-deficient animals, albeit at lower levels, in agreement with the later age of onset of this muscular dystrophy. The inflammatory proteins Spp1 and S100a9 were up-regulated in all models, including sarcospan-deficient mice, which points, for the first time, at a subtle phenotype for Sspn null mice. In conclusion, we identified biomarker genes for which expression correlates with the severity of the disease, which can be used for monitoring disease progression. This comparative study is an integrating step toward the development of an expression profiling-based diagnostic approach for muscular dystrophies in humans.
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PMID:Common pathological mechanisms in mouse models for muscular dystrophies. 1630 63

Duchenne muscular dystrophy (DMD) is a genetic disorder that causes progressive muscle weakness, ultimately leading to early mortality in affected teenagers and young adults. Previous work from our lab has shown that a small transmembrane protein called sarcospan (SSPN) can enhance the recruitment of adhesion complex proteins to the cell surface. When human SSPN is expressed at three-fold levels in mdx mice, this increase in adhesion complex abundance improves muscle membrane stability, preventing many of the histopathological changes associated with DMD. However, expressing higher levels of human SSPN (ten-fold transgenic expression) causes a severe degenerative muscle phenotype in wild-type mice. Since SSPN-mediated stabilization of the sarcolemma represents a promising therapeutic strategy in DMD, it is important to determine whether SSPN can be introduced at high levels without toxicity. Here, we show that mouse SSPN (mSSPN) can be overexpressed at 30-fold levels in wild-type mice with no deleterious effects. In mdx mice, mSSPN overexpression improves dystrophic pathology and sarcolemmal stability. We show that these mice exhibit increased resistance to eccentric contraction-induced damage and reduced fatigue following exercise. mSSPN overexpression improved pulmonary function and reduced dystrophic histopathology in the diaphragm. Together, these results demonstrate that SSPN overexpression is well tolerated in mdx mice and improves sarcolemma defects that underlie skeletal muscle and pulmonary dysfunction in DMD.
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PMID:High levels of sarcospan are well tolerated and act as a sarcolemmal stabilizer to address skeletal muscle and pulmonary dysfunction in DMD. 2779 7