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

The genes encoding enzymes involved in fatty acid metabolism are regulated by sterols. Stearoyl CoA desaturase, a key enzyme in the synthesis of unsaturated fatty acyl-CoAs is transcriptionally regulated by fat-free diet and sterols. To identify other genes that are induced in rat liver by fat-free diet we performed an in vivo gene expression profile analysis using DNA microarrays. Here we report that among the genes highly expressed is emerin, an integral protein of the inner nuclear membrane. Mutated or nonexpressed emerin occurs in patients with muscular dystrophy. Sterol regulatory element binding proteins activate the transcription of several sterol regulated genes. To investigate whether sterol regulatory element binding proteins or indirectly cholesterol activates the transcription of stearoyl CoA desaturase and emerin, we cultured Chinese hamster ovary (CHO), either in cholesterol-rich or cholesterol-depleted mediums. We also transiently transfected the cell culture with plasmid encoding sterol regulatory element binding proteins in cholesterol-rich medium. Our data show that cholesterol-supplemented media as well as the transient transfection induced the expression of stearoyl CoA desaturase RNA 3.5- and 7-fold respectively. However, the RNA level of emerin was not altered under these conditions, implying that the parallel induction of emerin is independent of the sterol regulatory element binding regulation pathway.
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PMID:Induction of stearoyl CoA desaturase is associated with high-level induction of emerin RNA. 1135 37

Arrhythmia and cardiomyopathy frequently accompany muscular dystrophy. In the last year, the cardiovascular consequences of muscular dystrophy gene mutations have been established through studies of murine models. These models have highlighted the potential role of primary defects in cardiac muscle as well as those secondary cardiovascular outcomes that arise from severe muscle disease. This review focuses on three areas. Recent studies using mouse models have shown that the dystrophin-associated proteins, the sarcoglycans and alpha-dystrobrevin, are critical for both cardiac and skeletal muscle membrane function, yet may exert their roles by different molecular mechanisms. New findings have shown that cytoskeletal proteins at the nuclear membrane, such as emerin and lamin AC, cause muscular dystrophy and cardiomyopathy with cardiac conduction system disease. Finally, the mechanism of cardiac and muscle degeneration in myotonic dystrophy has been re-evaluated through a series of studies using murine models. Implications for human therapy are considered in light of these new findings.
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PMID:Cardiomyopathy in animal models of muscular dystrophy. 1135 18

Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in the LMNA gene, which encodes lamin A and lamin C. Mutations in this gene also give rise to limb girdle muscular dystrophy type 1B, dilated cardiomyopathy with atrioventricular conduction defect and Dunnigan-type partial lipodystrophy. The properties of the mutant lamins that cause muscular dystrophy, lipodystrophy and dilated cardiomyopathy are not known. We transfected C2C12 myoblasts with cDNA encoding wild-type lamin A and 15 mutant forms found in patients affected by these diseases. Immunofluorescence microscopy showed that four mutants, N195K, E358K, M371K and R386K, could have a dramatically aberrant localization, with decreased nuclear rim staining and formation of intranuclear foci. The distributions of endogenous lamin A/C, lamin B1 and lamin B2 were also altered in cells expressing these four mutants and three of them caused a loss of emerin from the nuclear envelope. In the yeast two-hybrid assay, the 15 lamin A mutants studied interacted with themselves and with wild-type lamin A and lamin B1. Pulse-chase experiments showed no decrease in the stability of several representative lamin A mutants compared with wild-type. These results indicate that some lamin A mutants causing disease can be aberrantly localized, partially disrupt the endogenous lamina and alter emerin localization, whereas others localize normally in transfected cells.
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PMID:Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. 1179 9

Mutations in the genes encoding the inner nuclear membrane proteins lamin A/C and emerin produce cardiomyopathy and muscular dystrophy in humans and mice. The mechanism by which these broadly expressed gene products result in tissue-specific dysfunction is not known. We have identified a protein of the inner nuclear membrane that is highly expressed in striated and smooth muscle. This protein, myne-1 (myocyte nuclear envelope), is predicted to have seven spectrin repeats, an interrupted LEM domain and a single transmembrane domain at its C-terminus. We found that myne-1 is expressed upon early muscle differentiation in multiple intranuclear foci concomitant with lamin A/C expression. In mature muscle, myne-1 and lamin A/C are perfectly colocalized, although colocalization with emerin is only partial. Moreover, we show that myne-1 and lamin A/C coimmunoprecipitate from differentiated muscle in vitro. The muscle-specific inner nuclear envelope expression of myne-1, along with its interaction with lamin A/C, indicates that this gene is a potential mediator of cardiomyopathy and muscular dystrophy.
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PMID:Myne-1, a spectrin repeat transmembrane protein of the myocyte inner nuclear membrane, interacts with lamin A/C. 1180 24

Complex diagnosis of muscular dystrophies including clinical, bioptical and molecular genetic approaches has been provided in a limited extent in this country. Our group of neurologists, pathologists and geneticists has examined approximately 240 patients suspected of having muscular dystrophies, mostly coming from Southern and Northern Moravia. The patients were sent to the examination most often from departments of neurology and clinical genetics, and less frequently from departments of internal medicine. According to the final diagnosis, the patients were divided into groups: with dystrophinopathies and carriers of dystrophinopathies (DMD/BMD), merosin deficient form of congenital muscular dystrophy, and Emery-Dreifuss muscular dystrophy including the carriers of this disease. Some relatives of patients with dystrophinopathies were also examined using the methods of segregation analysis. High proportion of the DMD/BMD patients can be detected by the methods of molecular genetics. Analysis of mRNA using RT PCR and PTT enables the detection of deletions, duplications, and point mutations in dystrophin gene and encompasses a larger diagnostic scope in comparison with examinations of DNA level by the multiplex PCR method from the peripheral blood which enables only deletion detections. Immunophenotyping of the dystrophin protein plays an important role especially using antibodies against carboxyterminal (DYS2) and rod domain (DYS1) of dystrophin. Deficient sarcolemmal expression of DYS2 and DYS1 reveals unambiguously a pathological dystrophin. On the other hand, less pronounced deficiencies in dystrophin expression in BMD patients and DMD/BMD carriers may not always be detected in muscle biopsies. In this case, it is necessary to supplement the examination by Western blotting and genotype analysis. The examination of patients with clinically diagnosed muscular dystrophy should start with a muscle biopsy which enables the estimation of presence and degree of structural changes. Application of antibodies against the components of DGC and emerin may reveal a deficiency in expression of these proteins. Immunohistochemical examination completed by Western blotting leads to the subsequent molecular genetic analysis of DNA or mRNA. Secondary deficiencies in expression of other DGC proteins are often revealed in muscle biopsies of dystrophinopathies and this fact must be taken into account in the evaluation of immunohistochemical findings. There is a possibility of replacement of invasive muscle biopsy by skin biopsy or buccal mucosal smears in cases of merosin and emerin deficiencies. Commercially available antibodies against merosin, emerin, calpain and sarcoglycans enable extensive identification and detailed classification of muscular dystrophies. Screening of the patients based on the application of methods described and discussed in this report is the task of the forthcoming period.
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PMID:[Muscular dystrophies detected by immunophenotyping and genotype analysis (mRNA and DNA)]. 1181 30

The present review summarizes recent cytochemical findings on the functional organization of the nuclear domains, with a particular emphasis on the relation between nuclear envelope-associated proteins and chromatin. Mutations in two nuclear envelope-associated proteins, emerin and lamin A/C cause the Emery-Dreifuss muscular dystrophy; the cellular pathology associated with the disease and the functional role of emerin and lamin A/C in muscle cells are not well established. On the other hand, a large body of evidence indicates that nuclear envelope-associated proteins are involved in tissue-specific gene regulation. Moreover, chromatin remodeling complexes trigger gene expression by utilizing the nuclear matrix-associated actin, which is known to interact with both emerin and lamin A/C. It is thus conceivable that altered expression of these nuclear envelope-associated proteins can account for an impairment of gene expression mainly during cell differentiation as suggested by recent experimental findings on the involvement of emerin in myogenesis. The possibility that Emery-Deifuss muscular dystrophy pathogenesis could involve alteration of the signaling pathway is considered.
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PMID:Immunocytochemistry of nuclear domains and Emery-Dreifuss muscular dystrophy pathophysiology. 1268 53

Limb girdle muscular dystrophy (LGMD) type 2B and distal Miyoshi myopathy (MM) are caused by mutations in a recently discovered mammalian gene coding for a skeletal muscle protein called dysferlin. The protein is normally expressed at the skeletal muscle level and absent or reduced in affected patients. We selected a clinically heterogeneous population of Italian myopathic patients with clinical evidence of myopathy and/or hyperCKemia, EMG myopathic pattern, and no alterations of the dystrophin-sarcoglycan complex. Calpain, merosin, emerin and caveolin were also tested and found normal in all patients. Dysferlin immunohistochemical and Western blot analyses allowed us to identify six patients with dysferlin deficiency: one with distal myopathy, four with limb girdle myopathy and one with hyperCKemia. No apoptosis was found in any of the six muscle specimens, although expression of the pro-apoptotic Fas antigen was mildly increased in two cases. Inflammatory reactions were present in two of the six cases, but we found no evidence of immune-mediated processes.
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PMID:Clinical, morphological and immunological evaluation of six patients with dysferlin deficiency. 1273 59

The experience of DNA-diagnosis of X-linked recessive Emery-Dreifuss muscular dystrophy for the first time made in Russia is presented. A search for mutations in emerin gene responsible for the disease has been conducted in 13 blood samples of male patients with clinical diagnosis of various muscular dystrophy. Mutations were found in 2 patients. In one of them clinical diagnosis of Emery-Dreifuss muscular dystrophy was confirmed. In the other, a novel mutation was described that allowed to change a clinical diagnosis of limb girdle muscular dystrophy. X-linked and clinically identical autosomal-dominant forms of Emery-Dreifuss muscular dystrophy are characterized by pronounced clinical polymorphism complicating clinical diagnosis. DNA-diagnosis principally extends possibilities for early diagnosis of this disorder that is extremely important for prevention of severe and frequently lethal heart diseases.
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PMID:[DNA-diagnosis of Emery-Dreifuss muscular dystrophy]. 1287 22

An understanding of muscle structure and function is central to improving our knowledge of the group of muscle diseases referred to as muscular dystrophies. These diseases involve a progressive weakening and wasting of skeletal muscle, which can be associated with life-threatening cardiac arrhythmias. The vast majority of these diseases arise from defects in either cytoskeletal or structural proteins, resulting in a breakdown of muscle cell integrity. However, mutations in two nuclear proteins--emerin and lamin A/C--have also been demonstrated to give rise to a muscular dystrophy phenotype. In addition, mutations in lamin A/C can give rise to a dilated cardiomyopathy, a lipodystrophy or a neuropathy. It is far from clear how mutations in nuclear proteins can result in a dystrophy, or cause more than one clinically distinct disease. Understanding the functional role of nuclear proteins in causing these diseases will therefore provide novel insights into muscle function, and should hopefully provide new directions for treatment.
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PMID:Muscular dystrophies, dilated cardiomyopathy, lipodystrophy and neuropathy: the nuclear connection. 1458 57

Laminopathies are now recognized as a group of disorders due to mutations of the LMNA gene, which encodes A-type lamins. Primarily, mutations in LMNA have been associated to the autosomal forms of Emery-Dreifuss muscular dystrophy, a rare slowly progressive humero-peroneal muscular dystrophy accompanied by early contractures and dilated cardiomyopathy with conduction defects. LMNA mutations have been reported to be responsible for up to 10 distinct phenotypes that affect specifically either the skeletal and/or cardiac muscle, the adipose tissue, the peripheral nervous tissue, the bone tissue or more recently premature ageing. So far more than 180 different LMNA mutations have been identified in 903 individuals. The first studies of phenotype/genotype relationships revealed no dear relation between the phenotype and the type and/or the localization of the mutation, except perhaps for the globular tail domain of lamins A/C. Studies of the consequences of LMNA mutations in the skin cultured fibroblasts from the patients reveal abnormal nuclei in variable proportions, with dysmorphic nuclei exhibiting abnormal patterns of expression of B-type lamins and emerin. Finally, the development of KO and KI LMNA mice, will certainly give further insight into the pathophysiological mechanisms associated with LMNA mutations. For example, Lmna(H222P/H222P) mice harbour phenotypes reminiscent of Emery-Dreifuss muscular dystrophy.
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PMID:Genetics of laminopathies. 1577 49


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