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)

In various neuromuscular diseases, the most significant muscle degeneration is muscle fiber necrosis as seen in Duchenne muscular dystrophy (DMD). A certain membrane instability is probably responsible for muscle fiber necrosis, because defects in membrane proteins have been proposed to associate with progressive muscular dystrophies including dystrophin in DMD, a 50 KD subunit of dystrophin associated glycoprotein (DAG) in severe childhood autosomal recessive muscular dystrophy (SCARMD), and subunit M of laminin (merosin) in congenital muscular dystrophy and dy mouse. The vulnerable muscle surface membrane may permit extracellular calcium influx into the sarcoplasm resulting in focal myofibrillar hypercontraction (opaque fiber) and activation of proteases such as calpain and cathepsins. The muscle fiber then undergoes necrosis and allows macrophage invasion, followed by muscle fiber regeneration. Focal myofibrillar degeneration involving rimmed vacuole (RV) formation is an another striking muscle fiber degeneration seen in various neuromuscular diseases including inclusion body myositis (IBM) and distal myopathy with rimmed vacuole formation (DMRV). Abnormal accumulation of ubiquitin, beta-amyloid protein precursor and tau protein has been described in IBM by Askanas et al. The similar findings are also recognizable in DMRV and in an experimentally induced myopathy after long-term chloroquin administration to rat. Therefore, if we clarify the pathomechanism of degenerative process involved in the rimmed vacuole formation, the results may provide some insights into the understanding the process involved in amyloid plaque formation in Alzheimer's disease.
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PMID:[Muscle pathologic diagnosis--mechanism in muscle fiber degeneration]. 777 35

In a distinct autosomal recessive variant of epidermolysis bullosa, EB-MD, life-long skin blistering is associated with late-onset muscular dystrophy of unknown etiology. Electron microscopy of these patients' skin suggests that tissue separation occurs intracellularly at the level of the hemidesmosomal inner plaque, which contains plectin, a high molecular weight cytoskeletal associated protein, also expressed in the sarcolemma of the muscle. In this study, we report two patients with EB-MD, each with a homozygous deletion mutation in the plectin gene, PLEC1. In the first case, the proband and her similarly affected sister had a homozygous 9 bp deletion mutation, designated as 2719de19, which resulted in elimination of three amino acids, QEA, in a sequence of 23 amino acids entirely conserved between the mouse and human sequences. The proband in the second family demonstrated a single nucleotide deletion at position 5866, designated as 5866delC, which resulted in frameshift and a premature termination codon for translation 16 bp downstream from the site of deletion. The absence of plectin in the hemidesmosomes, as reflected by negative immunofluorescence with an anti-plectin antibody (HD-1), associated with fragility of basal keratinocytes, implicates plectin as critical for binding of intermediate keratin filament network to hemidesmosomal complexes. The function of plectin as a putative attachment protein also in the muscle would explain the clinical phenotype consisting of cutaneous fragility and muscular dystrophy in EB-MD.
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PMID:Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy. 889 87

Recent progress in understanding the molecular organization of the cutaneous basement membrane zone (BMZ) has revealed an intricate network of structural proteins necessary for stable association of the epidermis to the underlying dermis. Molecular genetics of the cutaneous BMZ has also revealed that defects in as many as nine distinct genes within the dermal-epidermal junction which result in different forms of epidermolysis bullosa (EB), a group of heritable mechano-bullous disorders. We have recently demonstrated that a variant of EB associated with late-onset development of muscular dystrophy (EB-MD, MIM no. 226670) results from mutations in the gene encoding plectin (PLEC1), a cytoskeleton associated attachment protein present in the hemidesmosomal inner plaque and the sarcolemma of the muscle. Consequently, mutations in this multi-functional gene/protein system can result in phenotypic manifestations of EB-MD both in the skin and the muscle. In this overview, we will summarize the domain organization of plectin and the structure of the corresponding gene (PLEC1), as well as the genetic basis of EB-MD in families studied thus far. Elucidation of the molecular basis of this subtype of EB adds to our understanding of the structural and functional complexity of the cutaneous BMZ.
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PMID:Plectin and human genetic disorders of the skin and muscle. The paradigm of epidermolysis bullosa with muscular dystrophy. 898 Oct 21

Plectin, a widespread cytoskeletal linker protein, is prominently expressed in basal keratinocytes of the epidermis. HD1, originally identified as a hemidesmosomal protein, has been suggested to be an isoform of or closely related to plectin, but the exact relationship between these proteins is unknown. Plectin has recently been identified as the gene/protein system at fault in epidermolysis bullosa simplex associated with muscular dystrophy (EBS-MD; OMIM# 226670). In this study, we examined the expression patterns of plectin and HD1 epitopes in the skin of four unrelated patients with EBS-MD confirmed to be caused by plectin gene mutations. By indirect immunofluorescence, all monoclonal antibodies (mAbs) to plectin (5B3, 10F6) or to HD1 (121, E2, K15, 156) bound to the epidermal basement membrane zone (BMZ) of normal human skin. In addition, immunostaining along the periphery of keratinocytes was detected with mAbs 5B3, 10F6 (antiplectin), K15 and 156 (anti-HD1), but not with mAbs 121 and E2 (anti-HD1). Immunolabeling for mAbs 5B3 and 10F6 (antiplectin) was absent in the skin of three patients who had premature termination codon mutations in the plectin gene in both alleles. In contrast, labeling was only slightly reduced in a patient who was homozygous for a 9-bp in-frame deletion mutation in the same gene. Interestingly, peripheral labeling of keratinocytes using mAbs K15 and 156 (anti-HD1) was clearly present in all the patients despite the disappearance of BMZ labeling. Quantitative analysis by postembedding immunoelectron microscopy demonstrated that both plectin and HD1 epitopes were localized in the inner plaque of hemidesmosomes with a mean distance of 110 and 120 nm from the plasma membrane, respectively. These results confirm the molecular heterogeneity of EBS-MD in terms of the expression patterns of plectin and HD1 epitopes which correlate with clinical severity, the pattern of plectin gene mutations and their consequences.
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PMID:Expression of plectin and HD1 epitopes in patients with epidermolysis bullosa simplex associated with muscular dystrophy. 1055 10

Caveolae and their coat proteins, caveolins (Cav), are cave-like invaginations found in the plasma membrane of a variety of cells. These unique vesicles and their coat proteins, Cavs, have diverse effects on endothelial function, nitric oxide synthesis regulation, signal transduction, cholesterol metabolism, and apoptosis. Animal studies in Cav knockout mice demonstrate the vital role of these structural proteins on endothelial and vascular function. Genetic studies have proposed that beside neoplasia, Cavs may play a role in the development of atherosclerosis, cardiomyopathy, long QT syndrome, pulmonary fibrosis, and muscular dystrophy. The role of Cav expression in atherosclerotic disease is poorly understood and remains controversial. Interestingly, there is emerging evidence between low Cav-1 levels and the vulnerable plaque, which could potentially identify Cav-1 as a novel plaque biomarker. Cavs, through intricate biochemical pathways involving endothelial nitric oxide synthase and mitogen-activated protein kinase, are known to affect the cardiovascular system at multiple levels. In the present review, we aim to highlight the nature and types of caveolae, caveolar signaling mechanisms and regulation, and the pathophysiology of Cavs as it pertains to the cardiovascular system. Ongoing research is needed to clarify the diagnostic and prognostic role of these novel proteins and to determine how the effects of Cavs can translate into clinical medicine.
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PMID:Myocardial tissue caveolae. 2588 May 16