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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the sarcoglycans. In particular, sarcospan was absent in a gamma-sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the gamma-sarcoglycan gene, which causes premature truncation of gamma-sarcoglycan without affecting assembly of the mutant gamma-sarcoglycan into a complex with alpha-, beta- and delta-sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of gamma-sarcoglycan is critical for the functioning of the entire sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper sarcoglycan-sarcospan expression and function.
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PMID:Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions. 1094 31

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is the most common cause of LGMD with a sarcoglycan defect. We recently engineered a murine model for this progressive disease and we investigated the possibility of preventing the development of muscular dystrophy in these animals by adenovirus-mediated gene transfer of human alpha-sarcoglycan. Here we report that a single intramuscular injection of a first generation adenovirus into the skeletal muscle of neonate mice led to sustained expression of alpha-sarcoglycan at the sarcolemma of transduced myofibers for at least 7 months. The morphology of transduced muscles was consequently preserved. In addition, we have used contrast agent-enhanced magnetic resonance imaging (MRI) to investigate sarcolemmal integrity in adenovirus-injected animals and have thereby demonstrated maintenance of sarcolemmal function. In conclusion, we provide evidence that early virus-mediated gene transfer of a sarcoglycan protein constitutes a promising therapeutic strategy for LGMDs and that the benefits of this approach can easily and effectively be monitored by noninvasive methodologies such as MRI.
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PMID:Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice. 1098 65

Dysferlin, the protein product of the gene mutated in patients with an autosomal recessive limb-girdle muscular dystrophy type 2B (LGMD2B) and a distal muscular dystrophy, Miyoshi myopathy, is homologous to a Caenorhabditis elegans spermatogenesis factor, FER-1. Analysis of fer-1 mutants and of sequence predictions of the FER-1 and dysferlin ORFs has predicted a role in membrane fusion. Otoferlin, another human FER-1-like protein (ferlin), has recently been shown to be responsible for autosomal recessive nonsyndromic deafness (DFNB9). In this report we describe the third human ferlin gene, FER1L3, which maps to chromosome 10q23.3. Expression analysis of the orthologous mouse gene shows ubiquitous expression but predominant expression in the eye, esophagus, and salivary gland. All the ferlins are characterized by sequences corresponding to multiple C2 domains that share the highest level of homology with the C2A domain of rat synaptotagmin III. They are predicted to be Type II transmembrane proteins, with the majority of the protein facing the cytoplasm anchored by the C-terminal transmembrane domain. Sequence and predicted structural comparisons have highlighted the high degree of similarity of dysferlin and FER1L3, which have sequences corresponding to six C2 domains and which share more than 60% amino acid sequence identity.
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PMID:The third human FER-1-like protein is highly similar to dysferlin. 1099 73

Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the pathogenesis of autosomal dominant limb girdle muscular dystrophy 1C. Here we report on a 4-year-old girl presenting with myalgia and muscle cramps due to a caveolin-3 deficiency in her dystrophic skeletal muscle as a result of a heterozygous 136G-->A substitution in the caveolin-3 gene. The novel sporadic missense mutation in the caveolin signature sequence of the caveolin-3 gene changes an alanine to a threonine (A46T) and prevents the localization of caveolin-3 to the plasma membrane in a dominant negative fashion. Caveolin-3 has been suggested to interact with the dystrophin-glycoprotein complex, which in striated muscle fibers links the cytoskeleton to the extracellular matrix and with neuronal nitric oxide synthase. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan expression was detected in the caveolin-3-deficient patient. These results implicate an important function of the caveolin signature sequence and common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies with caveolin-3-deficient limb girdle muscular dystrophy.
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PMID:Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. 1100 38

Muscular dystrophies represent a heterogeneous group of disorders, which have been largely classified by clinical phenotype. In the last 10 years, identification of novel skeletal muscle genes including extracellular matrix, sarcolemmal, cytoskeletal, cytosolic, and nuclear membrane proteins has changed the phenotype-based classification and shed new light on the molecular pathogenesis of these disorders. A large number of genes involved in muscular dystrophy encode components of the dystrophin-glycoprotein complex (DGC) which normally links the intracellular cytoskeleton to the extracellular matrix. Mutations in components of this complex are thought to lead to loss of sarcolemmal integrity and render muscle fibers more susceptible to damage. Recent evidence suggests the involvement of vascular smooth muscle DGC in skeletal and cardiac muscle pathology in some forms of sarcoglycan-deficient limb-girdle muscular dystrophy. Intriguingly, two other forms of limb-girdle muscular dystrophy are possibly caused by perturbation of sarcolemma repair mechanisms. The complete clarification of these various pathways will lead to further insights into the pathogenesis of this heterogeneous group of muscle disorders.
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PMID:Molecular basis of muscular dystrophies. 1100 81

Membrane lesions play an early role in the pathogenesis of muscular dystrophy. Using a new albumin-targeted contrast agent (MS-325), sarcolemmal integrity of two animal models for muscular dystrophy was studied by MRI. Intravenously injected MS-325 does not enter skeletal muscle of normal mice. However, mdx and Sgca-null mutant mice, animal models for Duchenne and sarcoglycan-deficient limb-girdle muscular dystrophy, respectively, showed significant accumulation of MS-325 in skeletal muscle. The results suggest that contrast agent-enhanced MRI could serve as a common, noninvasive imaging procedure for evaluating the localization, extent, and mechanisms of skeletal muscle damage in muscular dystrophy. Furthermore, this method is expected to facilitate assessment of therapeutic approaches in these diseases.
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PMID:Contrast agent-enhanced magnetic resonance imaging of skeletal muscle damage in animal models of muscular dystrophy. 1102 24

The limb-girdle muscular dystrophies are a highly heterogeneous group of muscle disorders with many different genetic causes now known. Amongst the causes of LGMD, the dysferlin gene stands out as novel for several reasons. It is the first known example of a C2 domain containing protein involved in a muscular dystrophy, mutations in the gene can be involved in a variable phenotype, and a naturally occurring mouse model for dysferlin deficiency has recently been identified. This article reviews the progress made in understanding this form of limb-girdle muscular dystrophy to date.
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PMID:Dysferlin and muscular dystrophy. 1109 85

Very recently, mutations within the LMNA gene on chromosome 1q21.2 were shown to result in forms of muscular dystrophy, conduction-system disease, cardiomyopathy, and partial lipodystrophy. The LMNA gene encodes for the nucleophilic A-type lamins, lamin A and lamin C. These isoforms are generated by different splicing within exon 10 of LMNA. Thus lamin A/C is, besides emerin, the first known nucleophilic protein which plays a role in human disease. To date, 41 different mutations, predominantly missense, in the LMNA gene are known causing variable phenotypes. Twenty-three different mutations of LMNA have so far been shown to cause autosomal-dominant Emery-Dreifuss muscular dystrophy (EDMD2), three mutations were reported to cause limb-girdle muscular dystrophy (LGMD1B), eight mutations are known to result in dilated cardiomyopathy (CMD1A), and seven mutations were reported to cause familial partial lipodystrophy (FPL). The reports of lamin mutations including the corresponding phenotype are of great interest in order to gain insights into the function of lamin A/C. Here we summarize the mutations published to date in LMNA encoding lamin A/C.
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PMID:Mutations in the LMNA gene encoding lamin A/C. 1110 73

Dysferlin has recently been identified as a novel gene involved in limb-girdle muscular dystrophy type 2B (LGMD2B) and its allelic disease, Miyoshi myopathy. The predicted structure of dysferlin suggests that it is a transmembrane protein possibly involved in membrane fusion. Thus, unlike previously identified structural proteins in muscular dystrophy, dysferlin is likely involved in a novel pathogenic mechanism for this disease. In this study, we have analyzed the expression of dysferlin in skeletal muscle of patients with disruptions in the dystrophin-glycoprotein complex and patients with a clinical diagnosis of LGMD2B or Miyoshi myopathy. We show expression of dysferlin at the sarcolemma in normal muscle and reduced sarcolemmal expression along with accumulation of intracellular staining in dystrophic muscle. Electron microscopy in Miyoshi myopathy biopsies suggests that the cytoplasmic staining could be a result of the abundance of intracellular vesicles. Our results indicate that dysferlin expression is perturbed in LGMD and that both mutations in the dysferlin gene and disruption of the dystrophin-glycoprotein complex can lead to the accumulation of dysferlin within the cytoplasm.
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PMID:Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb--girdle muscular dystrophies. 1111 47

Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. It was previously shown that defects in the human calpain 3 gene are responsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predominantly the proximal limb muscles. To better understand the function of calpain 3 and the pathophysiological mechanisms of LGMD2A and also to develop an adequate model for therapy research, we generated capn3-deficient mice by gene targeting. capn3-deficient mice are fully fertile and viable. Allele transmission in intercross progeny demonstrated a statistically significant departure from Mendel's law. capn3-deficient mice show a mild progressive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes. Affected muscles manifest a similar apoptosis-associated perturbation of the IkappaBalpha/nuclear factor kappaB pathway as seen in LGMD2A patients. In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations.
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PMID:Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice. 1113 85


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