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Clinical and Experimental Dermatology Jan 2003Non-Herlitz junctional epidermolysis bullosa (nH-JEB) is caused predominantly by mutations leading to premature stop codons on both alleles of the type XVII collagen... (Review)
Review
Non-Herlitz junctional epidermolysis bullosa (nH-JEB) is caused predominantly by mutations leading to premature stop codons on both alleles of the type XVII collagen gene (COL17A1). The analysis of mutations in this gene has provided a means of correlating genotype with phenotype of nH-JEB patients. The phenotype of nH-JEB is characterized by generalized blistering of skin and mucous membranes with atrophic scarring and nail dystrophy. Atrophic alopecia is a distinct feature of nH-JEB patients, but one that is not associated with the severity of the disease at other sites. Enamel hypoplasia and pitting of the teeth are also characteristic for nH-JEB and can be used to facilitate the correct diagnosis in children with a blistering skin disease. Analysis of the biological consequences of mutations in the COL17A1 gene has shown that most patients lack type XVII collagen mRNA due to nonsense-mediated mRNA decay. Patients with these mutations can therefore be a target for corrective gene therapy using vectors coding for full-length type XVII collagen. Proof of principle for this approach has recently been demonstrated. The analysis of naturally occurring phenomena of gene correction in the COL17A1 gene provides evidence for other mechanisms of gene correction in genetic diseases. For example, exclusion of an exon carrying a mutation can lead to a milder phenotype of nH-JEB than predicted by the original mutation. In addition, we have gained data suggesting that COL17A1 exons harbouring pathogenic mutations can also be repaired by trans-splicing, i.e. aligning corrected RNA sequences to introns in the vicinity of faulty exons in the COL17A1 premtRNA.
Topics: Alopecia; Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Dental Enamel Hypoplasia; Dystonin; Epidermolysis Bullosa; Genetic Therapy; Genotype; Humans; Models, Genetic; Mutation; Nerve Tissue Proteins; Non-Fibrillar Collagens; Phenotype; RNA Splicing; Collagen Type XVII
PubMed: 12558632
DOI: 10.1046/j.1365-2230.2003.01192.x -
Der Hautarzt; Zeitschrift Fur... Dec 1994Paraneoplastic pemphigus (PP) is a newly reported autoimmune disease, which is always associated with an underlying neoplasia. It is characterized by painful mucosal... (Review)
Review
Paraneoplastic pemphigus (PP) is a newly reported autoimmune disease, which is always associated with an underlying neoplasia. It is characterized by painful mucosal erosions and ulcerations, and by polymorphous skin lesions reminiscent of erythema multiforme, pemphigus vulgaris and lichen planus pemphigoides. These patients have autoantibodies that bind to a distinct complex of epidermal proteins, including desmoplakin I (250 kD), major bullous pemphigoid antigen (230 kD), desmoplakin II (210 kD) and a 190-kD and a 170-kD protein, neither of which has yet been further characterized. Histological findings include acantholysis, epidermal cell necrosis, vacuolar interface changes and, sometimes, lichenoid infiltrates of the upper dermis. Direct immunofluorescence shows an intercellular deposition of immunoreactants in the epidermis and granular deposits at the dermal-epidermal junction. Indirect immunofluorescence with rodent bladder as substrate shows an intercellular pattern. This method is the most convenient and cost-effective method of screening for PP, since antigens of both pemphigus vulgaris and pemphigus foliaceus are not expressed in this tissue.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantigens; Carrier Proteins; Child; Collagen; Cytoskeletal Proteins; Desmoplakins; Dystonin; Female; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Molecular Weight; Nerve Tissue Proteins; Non-Fibrillar Collagens; Paraneoplastic Syndromes; Pemphigus; Skin; Collagen Type XVII
PubMed: 7843961
DOI: 10.1007/s001050050181 -
Pediatric Dermatology Mar 2021Epidermolysis bullosa simplex (EBS) is a heterogeneous group of inherited disorders characterized by skin fragility due to intraepidermal separation. Most cases result... (Review)
Review
BACKGROUND
Epidermolysis bullosa simplex (EBS) is a heterogeneous group of inherited disorders characterized by skin fragility due to intraepidermal separation. Most cases result from heterozygous mutations in KRT5 or KRT14; however, a minority of affected individuals carry mutations in non-keratin genes including DST encoding an epithelial isoform of dystonin. DST-associated EBS is transmitted as an autosomal recessive trait. Here, we report a series of EBS patients carrying bi-allelic DST mutations and review previously reported cases aiming to delineate phenotype-genotype correlations.
METHODS
Whole-exome and direct sequencing were used for variant analysis. Review of previously reported cases was performed.
RESULTS
Mutation analysis revealed DST mutations in five patients belonging to three families. Two variants have not been previously reported: c.7097dupA (p.Tyr2366X) and c.7429delC (p.Leu2477Serfs*13). We identified an additional six cases in the literature, bringing the total number of individuals affected with EBS due to DST variants to 11. Patients displayed distinctive phenotypes regardless of the causative variant.
CONCLUSIONS
The current study expands the clinical and genetic spectrum of DST-associated EBS subtype.
Topics: Dystonin; Epidermolysis Bullosa Simplex; Humans; Keratin-14; Keratin-5; Mutation; Phenotype
PubMed: 33471381
DOI: 10.1111/pde.14477 -
The American Journal of Dermatopathology Apr 1999Routine histologic study usually is insufficient to subclassify epidermolysis bullosa (EB); currently, electron microscopic evaluation has been the gold standard. A... (Review)
Review
Routine histologic study usually is insufficient to subclassify epidermolysis bullosa (EB); currently, electron microscopic evaluation has been the gold standard. A major advance recently has been made in elucidating the molecular basis of several major forms of EB. Concomitantly, immunoreagents have been developed to map antigens in the basement membrane zone. Some of these reagents facilitate the classification of EB into types and subtypes and can be used as an adjunct informative screening procedure to direct mutation identification efforts using DNA technologies. The current review provides an overview of these recent developments and a more detailed account of the immunohistopathologic diagnosis of EB.
Topics: Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Diagnosis, Differential; Dystonin; Epidermolysis Bullosa; Epidermolysis Bullosa Simplex; Epidermolysis Bullosa, Junctional; Humans; Immunohistochemistry; Intermediate Filament Proteins; Microscopy, Electron; Nerve Tissue Proteins; Non-Fibrillar Collagens; Plectin; Skin; Collagen Type XVII
PubMed: 10218683
DOI: 10.1097/00000372-199904000-00015 -
Journal of the American Academy of... Nov 2019
Topics: Autoantibodies; Dystonin; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prognosis; Pruritus
PubMed: 31374311
DOI: 10.1016/j.jaad.2019.06.1314 -
Journal of the American Academy of... Aug 2022Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Its presentation is polymorphic.
BACKGROUND
Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Its presentation is polymorphic.
OBJECTIVE
To investigate different clinical and biological profiles of BP.
METHODS
We conducted a retrospective 2-center study including all BP patients seen between January 1, 2015, and February 28, 2021. We performed hierarchical clustering on principal components.
RESULTS
Three clusters were identified. Patients in cluster 1 (n = 155) were older than those in clusters 2 (n = 89) and 3 (n = 35; P < .0001), more frequently presented pauci-bullous BP (n = 63 [41%] vs 14 [16%] and 2 [6%], respectively; P < .0001) and had anti-BP230 antibodies in 87% of cases. More than 100 blisters were observed in 14 patients (40%) from cluster 3, versus 3 (2%) from cluster 1 and 0 (0%) from cluster 2 (P < .0001). Frequency of mucosal involvement was higher in cluster 3 (n = 32 [91%, including epiglottis in 40%] vs 11 [7%] and 34 [38%]; P < .0001). In clusters 2 and 3, 70% and 74% of patients had antibodies targeting only BP180. Those in cluster 3 received more lines of systemic treatment and experienced more relapses.
LIMITATIONS
Retrospective study without immunoelectron microscopy.
CONCLUSION
We identified 3 different BP clusters, including one corresponding to severe BP180 BP230 BP with features common to mucous membrane pemphigoid.
Topics: Autoantibodies; Autoantigens; Blister; Dystonin; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Retrospective Studies
PubMed: 35483492
DOI: 10.1016/j.jaad.2022.04.029 -
The Journal of Investigative Dermatology Nov 2022
Topics: Humans; Pemphigoid, Bullous; Non-Fibrillar Collagens; Dystonin; Autoantigens; Autoantibodies; Enzyme-Linked Immunosorbent Assay
PubMed: 35671826
DOI: 10.1016/j.jid.2022.05.1084 -
Clinics in Dermatology 1987
Review
Topics: Autoantibodies; Autoantigens; Basement Membrane; Carrier Proteins; Collagen; Cytoskeletal Proteins; Dystonin; Humans; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Skin; Skin Diseases, Vesiculobullous; Collagen Type XVII
PubMed: 3552197
DOI: 10.1016/0738-081x(87)90054-x -
Methods in Enzymology 2016Plectin and BPAG1e belong to the plakin family of high-molecular-weight proteins that interconnect the cytoskeletal systems and anchor them to junctional complexes....
Plectin and BPAG1e belong to the plakin family of high-molecular-weight proteins that interconnect the cytoskeletal systems and anchor them to junctional complexes. Plectin and BPAG1e are prototypical plakins with a similar tripartite modular structure. The N- and C-terminal regions are built of multiple discrete structural domains, while the central rod domain mediates dimerization by coiled-coil interactions. Owing to the mosaic organization of plakins, the structure of their constituent individual domains or small multi-domain segments can be analyzed isolated. Yet, understanding the integrated function of large regions, oligomers, and heterocomplexes of plakins is difficult due to the large and segmented structure. Here, we describe methods for the production of plectin and BPAG1e samples suitable for structural and biophysical analysis. In addition, we discuss the combination of hybrid methods that yield information at several resolution levels to study the complex, multi-domain, and flexible structure of plakins.
Topics: Carrier Proteins; Crystallography, X-Ray; Cytoskeletal Proteins; Dystonin; Escherichia coli; Humans; Models, Molecular; Nerve Tissue Proteins; Peptide Fragments; Plectin; Protein Structure, Secondary; Scattering, Small Angle
PubMed: 26778559
DOI: 10.1016/bs.mie.2015.05.002 -
Dermatologica 1987The zone of human skin between the epidermis and dermis is called the dermal-epidermal junction (DEJ). The importance of the DEJ is outlined and three new areas of... (Review)
Review
The zone of human skin between the epidermis and dermis is called the dermal-epidermal junction (DEJ). The importance of the DEJ is outlined and three new areas of research involving the DEJ are reviewed: the intracellular pool of bullous pemphigoid antigen, the interactions between fibronectin and keratinocytes and the epidermolysis bullosa acquisita antigen.
Topics: Autoantigens; Basement Membrane; Carrier Proteins; Cell Membrane Permeability; Collagen; Connective Tissue; Cytoskeletal Proteins; Dystonin; Epidermal Cells; Epidermis; Epidermolysis Bullosa; Extracellular Matrix; Fibronectins; Humans; Laminin; Nerve Tissue Proteins; Non-Fibrillar Collagens; Skin; Skin Physiological Phenomena; Collagen Type XVII
PubMed: 3542613
DOI: 10.1159/000248972