Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Plectin is one of the largest and most versatile cytolinker proteins known. In basal keratinocytes it links the intermediate filament network to cell membrane-associated hemidesmosomes. Several mutations in its gene have been identified that lead to the recessive disease epidermolysis bullosa with muscular dystrophy. We report here a mutation that leads to a dominant form of the disease, epidermolysis bullosa simplex Ogna. We found that the epidermolysis bullosa simplex Ogna phenotype is due to a site-specific missense mutation within plectin's rod domain. Further, we show that epidermolysis bullosa simplex Ogna is not restricted to a single Norwegian kindred as previously believed. A German family with the phenotypic hallmarks of epidermolysis bullosa simplex Ogna was found to carry an identical de novo mutation. These two mutations arose about 200 y apart in time. Consistent with the absence of muscular symptoms in these patients, muscle biopsies from several epidermolysis bullosa simplex Ogna members of the Norwegian kindred showed normal staining patterns using antibodies to plectin. Skin changes in epidermolysis bullosa simplex Ogna patients are documented on the ultrastructural level.
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PMID:A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. 1185 80

Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or alpha-B-crystallinopathies.
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PMID:Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy. 1207 35

Plectin is a high molecular mass protein (ca 530 kDa) that binds actin, intermediate filaments, and microtubules. Mutations of the human plectin gene cause epidermolysis bullosa simplex with muscular dystrophy. In mature human skeletal muscle, plectin is localized between neighboring myofibrils and between myofibrils and the sarcolemma, both at the level of Z-discs. In the present study we have analyzed plectin expression patterns with emphasis on its sarcolemmal localization during human skeletal muscle differentiation in vitro. In myoblasts plectin showed a cytoplasmic intermediate filament-like distribution, whereas in myotubes plectin is also found at the level of the sarcolemma. In particular, in early myotubes a specific plectin isoform colocalizes with the costameric proteins vinculin and beta1D integrin in longitudinally orientated structures which increased in number and longitudinal extension upon further maturation. In mature myotubes processes perpendicular to the parallel system of longitudinal structures became apparent. Subsequent to the occurrence of spontaneous myofibrillar contractions, the number of longitudinal streaks decreased, and plectin and other costameric proteins were found in an orderly cross-striated sarcolemmal lattice overlying myofibrillar Z-discs. Our study demonstrates that plectin is preassembled together with vinculin and beta1D integrin into primary longitudinal adhesion structures. After the occurrence of spontaneous contractions, these structures reorient and mature costameres are assembled.
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PMID:Primary longitudinal adhesion structures: plectin-containing precursors of costameres in differentiating human skeletal muscle cells. 1237 26

Plectin is a versatile cytoskeletal linker protein that preferentially localizes at interfaces between intermediate filaments and the plasma membrane in muscle, epithelial cells, and other tissues. Its deficiency causes muscular dystrophy with epidermolysis bullosa simplex. To better understand the functional roles of plectin beneath the sarcolemma of skeletal muscles and to gain some insights into the underlying mechanism of plectin-deficient muscular dystrophy, we studied in vivo structural and molecular relationships of plectin to subsarcolemmal cytoskeletal components, such as desmin, dystrophin, and vinculin, in rat skeletal muscles. Immunogold electron microscopy revealed that plectin fine threads tethered desmin intermediate filaments onto subsarcolemmal dense plaques overlying Z-lines and I-bands. These dense plaques were found to contain dystrophin and vinculin, and thus may be the structural basis of costameres. The in vivo association of plectin with desmin, (meta-)vinculin, dystrophin, and actin was demonstrated by immunoprecipitation experiments. Treatment of plectin immunoprecipitates with gelsolin reduced actin, dystrophin, and (meta-)vinculin but not desmin, implicating that subsarcolemmal actin could partly mediate the interaction between plectin and dystrophin or (meta-)vinculin. Altogether, our data suggest that plectin, along with desmin intermediate filaments, might serve a vital structural role in the stabilization of the subsarcolemmal cytoskeleton.
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PMID:Plectin tethers desmin intermediate filaments onto subsarcolemmal dense plaques containing dystrophin and vinculin. 1261 Jul 30

Genetic abnormalities for different subtypes of epidermolysis bullosa (EB) have been described. In dominant simplex type EB, mutations of the K5 or K14 gene lead to disruption of basal cells and the formation of bullae. The recessive simplex types include EB with muscular dystrophy due to abnormal plectin, EB without muscular dystrophy in patients homozygous for K14 gene abnormalities, and skin fragility syndrome, with formation of acantholytic vesicles within the epidermis due to PKP1 gene mutations. In junctional EB, mutations of the laminin 5, type XVII collagen, and alpha 6 beta 4 integrin genes have been reported. Dystrophic type EB is associated with various abnormalities of the type VII collagen gene. A new classification of EB based on these genetic abnormalities has been proposed. However, some concern has been voiced regarding the clinical utility of a classification based solely on genetic abnormalities. Although the reasons are unclear, identical genetic abnormalities have been known to be associated with different clinical features. A classification including a component based on clinical features would therefore be preferable. This article describes recently discovered genetic abnormalities and offers a new classification scheme for EB.
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PMID:Genetic abnormalities and clinical classification of epidermolysis bullosa. 1267 30

Genetic mutations in plectin, a cytoskeleton linker protein expressed in a large variety of tissues including skin, muscle, and nerves, cause epidermolysis bullosa simplex with muscular dystrophy, a recessive inherited disease characterized by blistering of the skin and late onset of muscular dystrophy, and Ogna epidermolysis bullosa simplex, a rare dominant inherited form of epidermolysis bullosa simplex with no muscular involvement. Here we report a novel homozygous genetic mutation (2727del14) in the plectin gene (PLEC1) associated with a lethal form of recessive inherited epidermolysis bullosa in a consanguineous family with three affected offspring. This new clinical variant of epidermolysis bullosa is characterized by general skin blistering, aplasia cutis of the limbs, developmental complications, and rapid demise after birth. Mutation 2727del14 is the first genetic defect described in PLEC1 that disrupts the plakin domain of plectin. The severe phenotype of the patients may be linked to the role of the N-terminal domain in the function of plectin and develops the understanding of the genotype-phenotype correlations in the genodermatoses affecting the dermal-epidermal junction.
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PMID:Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. 1467 80

Plectin is one of the largest and most versatile cytolinker proteins known. Cloned and sequenced in 1991, it was later shown to have nonsense mutations in recessive epidermolysis bullosa with muscular dystrophy. A dominant mutation in the gene was found to cause epidermolysis bullosa simplex Ogna without muscular dystrophy. Here we report the DNA sequencing of the plectin gene (PLEC1) in a Dutch family originally described in 1972 as having epidermolysis bullosa with muscular dystrophy. The results revealed homozygosity for a new plectin nonsense mutation at position 13187 and its specific 8q24 marker haplotype profile. Western blotting of cultured fibroblasts and immunofluorescence microscopy of skin biopsy confirm that the plectin protein expression is grossly reduced or absent. A summary of the life-long clinical course of the two affected brothers homozygous for the new E1914X mutation is given.
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PMID:Life-long course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation. 1520 92

Epidermolysis bullosa with pyloric atresia (EB-PA), manifesting with neonatal blistering and gastric anomalies, is known to be caused by mutations in the hemidesmosomal genes ITGA6 and ITGB4, which encode the alpha6 and beta4 integrin polypeptides, respectively. As part of our molecular diagnostics program, we have now encountered four families with EB-PA in which no mutations could be identified in these two genes. Instead, PCR amplification followed by heteroduplex scanning and/or direct nucleotide sequencing revealed homozygous mutations in the plectin gene (PLEC1), encoding another hemidesmosomal protein previously linked to EB with muscular dystrophy. Our findings provide evidence for additional molecular heterogeneity in EB, and emphasize the importance of screening EB-PA patients not only for alpha6beta4 integrin but also for plectin deficiency.
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PMID:Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. 1565 62

Epidermolysis bullosa (EB) is an inherited mechano-bullous disorder of the skin, and is divided into three major categories: EB simplex (EBS), dystrophic EB, and junctional EB (JEB). Mutations in the plectin gene (PLEC1) cause EBS associated with muscular dystrophy, whereas JEB associated with pyloric atresia (PA) results from mutations in the alpha6 and beta4 integrin genes. In this study, we examined three EB patients associated with PA from two distinct families. Electron microscopy detected blister formation within the basal keratinocytes leading to the diagnosis of EBS. Surprisingly, immunohistochemical studies using monoclonal antibodies to a range of basement membrane proteins showed that the expression of plectin was absent or markedly attenuated. Sequence analysis demonstrated four novel PLEC1 mutations. One proband was a compound heterozygote for a nonsense mutation of Q305X and a splice-site mutation of 1344G-->A. An exon-trapping experiment suggested that the splice-site mutation induced aberrant splicing of the gene. The second proband harbored a heterozygous maternal nonsense mutation, Q2538X and homozygous nonsense mutations R1189X. Analysis of the intragenic polymorphisms of PLEC1 suggested that R1189X mutations were due to paternal segmental uniparental isodisomy. These results indicate that PLEC1 is a possible causative gene in this clinical subtype, EBS associated with PA. Furthermore, two patients out of our three cases died in infancy. In terms of clinical prognosis, this novel subtype is the lethal variant in the EBS category.
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PMID:Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). 1568 71

Plectin, a large multidomain adhesive protein with versatile binding functions, is expressed in a number of tissues and cell types. In the skin, plectin is a critical component of hemidesmosomes, interacting with keratin intermediate filaments and beta4 integrin. Mutations in the plectin gene (PLEC1) result in fragility of skin, demonstrating blister formation at the level of hemidesmosomes. These blistering disorders belong to the spectrum of epidermolysis bullosa (EB) phenotypes, and three distinct variants because of plectin mutations have been identified. First, EB with muscular dystrophy, an autosomal recessive syndrome, is frequently caused by premature termination codon-causing mutations leading to the absence of plectin both in the skin and in the muscle. Second, a heterozygous missense mutation (R2110W) in PLEC1 has been documented in patients with EB simplex of the Ogna type, a rare autosomal dominant disorder. Finally, recent studies have disclosed plectin mutations in patients with EB with pyloric atresia, an autosomal recessive syndrome, frequently with lethal consequences. Collectively, these observations attest to the phenotypic spectrum of plectin mutations, and provide the basis for accurate genetic counselling with prognostic implications, as well as for prenatal diagnosis in families at the risk of recurrence of the disease.
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PMID:Progress in epidermolysis bullosa: the phenotypic spectrum of plectin mutations. 1581 Aug 81


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