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

Alterations in mitochondrial distribution and morphology are associated with normal cellular processes such as cell division and differentiation, as well as a variety of pathological conditions, including muscular dystrophy and cardiomyopathy. These observations have illuminated the necessity for a cellular machinery that mediates mitochondrial behavior and function. One important candidate member of this machinery is the cytoskeleton, all three members of which seem to associate with mitochondria. The role and significance of such association with the intermediate filament (IF) cytoskeleton in muscle was until recently completely unknown. Recent studies with desmin-deficient mice revealed the importance of desmin IFs in mitochondrial behavior and function. This review summarizes recent findings that link desmin cytoskeleton to muscle mitochondrial distribution and function. In particular, hypotheses are presented on the potential mechanism by which desmin's absence from cardiac muscle leads to abnormal mitochondrial behavior and compromised function, potentially responsible for the development of dilated cardiomyopathy and heart failure in desmin-null mice.
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PMID:Desmin cytoskeleton: a potential regulator of muscle mitochondrial behavior and function. 1253 20

Titin, the biggest single (poly) peptide found in humans, and throughout nature so far, was long considered as a good candidate for inherited muscle diseases. However, disease-causing defects were not known until recently, when this central sarcomeric protein was associated with human skeletal tibial muscular dystrophy (TMD/LGMD2J), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Several mutations in different parts of titin have now been identified and more are expected. Spontaneous mouse and zebrafish mutants have also been reported. Experimental knock-outs are not viable, even in cases where just a c-terminal part of the gene was silenced, telling something of the basic importance of titin for life. In this article we review the current known structure and functions of this elementary molecule with some emphasis on the only defects so far known to cause human skeletal muscle disease, mutations in the c-terminal M-line part of titin.
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PMID:The role of titin in muscular disorders. 1457 68

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

The human LMNA gene, when mutated, has been shown to cause at least 7 human diseases: dilated cardiomyopathy, Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, familial partial lipodystrophy, Charcot Marie tooth disease type II, mandibuloacral dysplasia, and Hutchinson-Gilford Progeria (OMIM #176670). This article describes a high-throughput method for screening the human lamin A/C (LMNA) gene for genetic mutations and sequence variation using denaturing high-performance liquid chromatography (DHPLC). In the present study, 76 patients with dilated cardiomyopathy were screened for mutations using DHPLC and sequence analysis. Abnormal elution profiles were identified and sequenced on an ABI 377 automatic sequencer. Heterozygous LMNA mutations were detected in 8% of the affected patients. In addition, a number of intronic and exonic single nucleotide polymorphisms were identified. LMNA mutations are clinically relevant in at least 6 human diseases. This study provides a protocol for high-throughput LMNA analysis applicable both in the research and in the clinical diagnostic setting.
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PMID:Analysis of genetic variations of lamin A/C gene (LMNA) by denaturing high-performance liquid chromatography. 1547 83

This study evaluated common clinical characteristics of patients with lamin A/C gene mutations that cause either isolated dilated cardiomyopathy or dilated cardiomyopathy in association with skeletal muscular dystrophy. We pooled clinical data of all published carriers of lamin A/C gene mutations as cause of skeletal and/or cardiac muscle disease and reviewed ECG findings. Cardiac dysrhythmias were reported in 92% of patients after the age of 30 years; heart failure was reported in 64% after the age of 50. Sudden death was the most frequently reported mode of death (46%) in both the cardiac and the neuromuscular phenotype. Carriers of lamin A/C gene mutations often received a pacemaker (28%). However, this intervention did not alter the rate of sudden death. Review of the ECG findings typically showed a low amplitude P wave and prolongation of the PR interval with a narrow QRS complex. This meta-analysis suggests that cardiomyopathy due to lamin A/C gene mutations portends a high risk of sudden death, and that this risk does not differ between subjects with predominantly cardiac or neuromuscular disease. This implies then that all carriers of a lamin A/C gene mutation need to be carefully screened with particular emphasis also on tachyarrhythmias. Prospective studies are needed to evaluate risk stratification and proper treatment strategies.
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PMID:Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? 1555 Oct 23

Emery-Dreifuss muscular dystrophy (EDMD) is a common form of muscular dystrophy frequently involving cardiac muscle, thus leading to dilated cardiomyopathy. Clinical outcome and prognosis is frequently determined by the involvement of the cardiac conduction system causing symptomatic bradyarrhythmias, as well as tachyarrhythmias and, if untreated, frequent sudden cardiac death. Typical features of the cardiac involvement of EDMD are presented, caused by a novel missense mutation in the splice receptor sequence of intron 6 of the LMNA gene on chromosome 1, encoding for the lamin A/C gene, consistent with the autosomal dominant form of EDMD.
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PMID:Cardiac involvement in Emery-Dreifuss muscular dystrophy. 1569 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

At least ten different diseases have been linked to mutations in proteins associated with the nuclear envelope (NE). Eight of these diseases are associated with mutations in the lamin A gene (LMNA). These diseases include the premature ageing or progeric diseases Hutchinson-Gilford progeria and atypical Werner's syndrome, diseases affecting striated and cardiac muscle including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting white fat deposition and skeletal development and a peripheral neuropathy resulting in motor neuron demyelination. To understand how these diseases arise from different mutations in the same protein, we established mouse lines carrying some of the same mutations found in the human LMNA gene, as both mouse and human lamin genes show a very high degree of sequence conservation. We have generated mice with different mutations resulting in progeria, muscular dystrophy and dilated cardiomyopathy. Our mouse lines are providing novel insights into how changes to the nuclear lamina affect the mechanical integrity of the nucleus and in turn intracellular signalling, such as the NF-kappaB pathway, as well as cell proliferation and survival, cellular functions that, when disrupted, may be the basis for the origin of such diseases.
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PMID:Mutations in the mouse Lmna gene causing progeria, muscular dystrophy and cardiomyopathy. 1577 58

The cardiomyocyte membrane cytoskeleton consists of the costameric proteins that mediate force transduction from the cell to the extracellular matrix, and a sub-membrane network composed of dystrophin and associated proteins. Studies of the precise cellular distribution of dystrophin and of the consequences of genetic mutations leading to abnormal expression of the dystrophin molecule, as occurs in Duchenne and Becker's muscular dystrophies, highlight potential functional roles of this sub-membrane protein complex in cardiomyocytes. Detailed investigation of dystrophin distribution using the complementary cell imaging techniques of immunoconfocal microscopy and freeze-fracture cytochemistry at the electron-microscopical level show that, in contrast to rat cardiomyocytes, the dystrophin network in human cardiomyocytes is locally enriched at costameres. Thus located, the dystrophin network appears to have a mechanical role, involving stabilization of the peripheral plasma membrane during the repetitive distortion associated with cardiac contraction and, in the human myocyte, contributing to lateral force-transduction. Evidence from animal models of muscular dystrophy and from investigation of the interactions of the sub-membrane cytoskeleton with other membrane-associated proteins including ion channels, receptors and enzymes, further suggests a role for dystrophin in organization and regulation of membrane domains. The relative preservation of the membrane cytoskeleton in non-dystrophic dilated cardiomyopathy and in ischemic cardiomyopathy, conditions in which the myocyte contractile apparatus and internal desmin-based cytoskeleton are commonly disrupted, emphasizes the vital role of the membrane cytoskeleton in cell survival. Continued cardiomyocyte survival despite loss of contractile protein organization has implications in the potential for reversibility of left ventricular remodeling that can be achieved in the clinical setting.
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PMID:Dystrophin and the cardiomyocyte membrane cytoskeleton in the healthy and failing heart. 1622 6

Myotonic dystrophies (DMs) encompass at least 2 forms: myotonic dystrophy type 1 and 2. In general, DMs are late-onset autosomal dominant disorders characterized by a variety of multisystemic features including myotonia, muscular dystrophy, cardiac conduction defects, dilated cardiomyopathy, posterior iridescent cataracts, frontal balding, insulin-resistance and disease-specific serological abnormalities such as gamma-glutamyltransferase and creatine kinase elevations, hyperglycemia, hypotestosteronism, and reduced immunoglobulin (Ig) G and IgM levels. Beyond the adult forms, in the classic DM1, a congenital form and an early-onset form is recognized. Here we summarize current aspects of the myotonic dystrophy pathogenesis and review the core features of both types of myotonic dystrophies, including the congenital DM1.
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PMID:Myotonic dystrophies type 1 and 2: a summary on current aspects. 1702 56


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