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)

Epidermolysis bullosa (EB) with late-onset muscular dystrophy (EB-MD) is a hemidesmosomal variant of EB due to mutations in the plectin gene (PLEC1). The age of onset of muscle involvement has been noted to vary from infancy to the fourth decade of life. Immunofluorescence of the patients' skin and muscle biopsies is usually negative for staining with antibodies recognizing plectin, a large cytoskeleton-associated anchorage protein. In this study we report novel plectin mutations in two families with EB. In both families, the proband was a newborn with neonatal blistering with no evidence for muscle weakness as yet. Peripheral blood DNA was isolated and examined by heteroduplex scanning strategy, protein truncation test (PTT), and/or direct sequencing of the plectin gene. One of the probands was compound heterozygote for nonsense mutations E2005X/K4460X, and the proband in the second family was compound heterozygote for deletion mutations 5083delG/2745-9del21, the latter mutation extending from -9 to +12 at the intron 22/exon 23 border. The mutations K4460X and 5083delG were not present in either one of the parents, thus being de novo events. In both cases, nonpaternity was excluded by microsatellite marker analysis. The stop codon mutations are predicted to result in the synthesis of a truncated protein lacking the carboxy-terminal globular domain of the protein and possibly causing nonsense-mediated decay of the corresponding mRNA. The 2745-9del21 deletion mutation abolishes the splice site at the intron 22/exon 23 junction, predicting abnormal splicing events. Because plectin deficiency is associated with muscular dystrophy, molecular diagnostics of the plectin gene provides prognostic value in evaluation of these patients who appear to be at risk to develop muscular dystrophy.
J Invest Dermatol 2000 Feb
PMID:Epidermolysis bullosa: novel and de novo premature termination codon and deletion mutations in the plectin gene predict late-onset muscular dystrophy. 1065 2

Epidermolysis bullosa simplex associated with late onset of muscular dystrophy has been found to show defective expression of plectin, an intracytoplasmic protein in hemidesmosomes. In this report, we examined ability of cell-to-matrix attachment of cultured keratinocytes derived from a case with this disease by various cell biological methods, and compared it to that of normal keratinocytes. In cell adhesion assay, the patient keratinocytes showed more prominent short-time cell adhesion than normal keratinocytes. In contrast, the patient keratinocytes could be detached much easier than normal keratinocytes in cell detachment assay by treatment with dispase. In phagokinetic track assay, no apparent difference of cell migration was observed between the patient and normal keratinocytes. These results indicate that plectin-deficiency may up-regulate short-term cell contact and reduce stable cell-matrix adhesion at the epidermal basement membrane zone.
J Dermatol Sci 2000 Dec
PMID:Cultured keratinocytes from plectin/HD1-deficient epidermolysis bullosa simplex showed altered ability of adhesion to the matrix. 1108

Anchoring complexes are specialized focal attachment sites within the cutaneous basement membrane zone (BMZ) and play a crucial role in dermo-epidermal adhesion. Structural weakness that may be caused by the binding of autoantibodies to components of the anchoring complex or by aberrant expression of these components as a result of genetic defects can lead to subepidermal blisters. Autoimmune subepidermal blistering disorders include bullous pemphigoid, pemphigoid gestationis, lichen planus pemphigoides, linear IgA disease, cicatricial pemphigoid, anti-p200, anti-p105, and anti-p450 pemphigoid, epidermolysis bullosa acquisita, and bullous systemic lupus erythematosus. The autoantigen in the skin of patients with dermatitis herpetiformis remains to be identified. More than 300 distinct mutations in 10 different genes corresponding to structural components of the BMZ have been described that result in skin fragility and dermo-epidermal separation associated with characteristic extracutaneous manifestations. This group of genodermatoses, collectively referred to as epidermolysis bullosa (EB), consists of distinct variants, such as EB simplex, EB with muscular dystrophy, EB with pyloric atresia, generalized atrophic benign EB, Herlitz junctional EB, and dystrophic EB. Recent advances in the molecular characterization of BMZ components have led to a better understanding of the interaction between these molecules as well as the autoimmune response against these proteins. In addition, by the elucidation of genetic defects in the different variants of EB, genotype-phenotype correlations now begin to arise and genetic counseling has been improved.
Adv Dermatol 2000
PMID:Autoimmune and inherited subepidermal blistering diseases: advances in the clinic and the laboratory. 1109 26

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.
J Invest Dermatol 2002 Jan
PMID:A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. 1185 80

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.
Arch Dermatol Res 2003 Apr
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.
J Invest Dermatol 2003 Dec
PMID:Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. 1467 80

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.
J Invest Dermatol 2005 Jan
PMID:Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. 1565 62

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.
Exp Dermatol 2005 Apr
PMID:Progress in epidermolysis bullosa: the phenotypic spectrum of plectin mutations. 1581 Aug 81

The efficient treatment of hereditary disorders, especially of those caused by dominant-negative mutations still remains an obstacle to be overcome. Allele specificity is a critical aspect that must be addressed by silencing therapies such as small interfering RNA, which has the potential risk of also reducing expression of the normal allele. To overcome this hurdle, we used spliceosome-mediated RNA trans-splicing (SMaRT) to replace mRNA exon segments in an in vitro disease model. In this model, a heterozygous insertion of a leucine codon into exon 9 of the plectin gene (PLEC1) leads to aggregation of plectin peptide chains and subsequent protein degradation recapitulating, together with a nonsense mutation on the other allele, the blistering skin disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Transient transfection of EBS-MD fibroblasts with a 5' pre-trans-splicing molecule encoding wild-type exons 2-9 led to specific replacement of the mutated 5' portion of the endogenous PLEC1 transcript through trans-splicing. This treatment reduced the levels of mutant mRNA and restored a wild-type pattern of plectin expression as revealed by immunofluorescence microscopy. When EBS-MD fibroblasts were transfected with retroviral constructs, the level of full-length plectin protein in the corrected fibroblasts increased by 58.7%. Thus, SMaRT may be a promising new tool for treatment of autosomal-dominant genetic diseases.
J Invest Dermatol 2008 Mar
PMID:5' trans-splicing repair of the PLEC1 gene. 1826 35

In this issue, Wally et al. (2008) report successful gene expression repair by spliceosome-mediated RNA trans-splicing (SMaRT), a novel achievement in molecular medicine. In their model, SMaRT was able to replace a mutation of the plectin gene in epidermolysis bullosa simplex with muscular dystrophy. This approach is particularly attractive for skin gene therapy of dominant-negative mutations present in a number of blistering genodermatoses.
J Invest Dermatol 2008 Mar
PMID:SMaRT technology enables gene expression repair in skin gene therapy. 1798 27


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