10 results on '"REVERTANT MOSAICISM"'
Search Results
2. Modified Non-Cultured Cell Spray Induced Epithelization in LAMB3 Mutation Epidermolysis Bullosa
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Widhiati S, Dewi ST, Yefta, Danarti R, Soebono H, Irmawati YE, Puspitasari M, Trisnowati N, Wibawa T, Purnomosari D, and Wirohadidjojo YW
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revertant mosaicism ,silver-sulfadiazine ,plastic wrap ,chronic wound ,junctional epidermolysis bullosa ,Dermatology ,RL1-803 - Abstract
Suci Widhiati,1,2 Shinta Trilaksmi Dewi,3 Yefta,3 Retno Danarti,3 Hardyanto Soebono,3 Yulia Eka Irmawati,3 Monika Puspitasari,3 Niken Trisnowati,3 Tri Wibawa,4 Dewajani Purnomosari,5 Yohanes Widodo Wirohadidjojo3 1Department of Dermatology and Venereology, Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia; 2Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; 3Department of Dermatology and Venereology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; 4Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; 5Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, IndonesiaCorrespondence: Yohanes Widodo Wirohadidjojo, Department of Dermatology and Venereology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Gedung Radiopoetro, lt. 3 Sekip, Yogyakarta, 55281, Indonesia, Tel +62 274 560700, Email yohanes.widodo@ugm.ac.idBackground: Autologous non-cultured cell (ANCC) spray has been used to treat burns, chronic wounds, and vitiligo, but its use in junctional epidermolysis bullosa (JEB) has not been published previously. Chronic wounds in JEB are caused by mutations of laminin 332 (L322), whose function is to attach and act as a glue in the basal membrane. It is proposed that ANCC applications can provide keratinocytes and fibroblasts required to improve epithelization and spontaneously correct revertant keratinocytes in the wound area.Purpose: To develop a modified procedure of ANCC spray and improve epithelization using silver sulfadiazine covered with plastic wrap to treat chronic wounds of JEB.Patients and Methods: Shave excision of the donor site was performed on a 19-year-old girl with JEB. The ANCC spray was prepared and applied to the chronic wound, which was then covered with silver sulfadiazine occluded with plastic wrap.Results: Following the ANCC spray application, epithelization was successfully initiated. Unfortunately, the wounds recurred after four months of follow-up.Conclusion: The modified application method of ANCC spray provides a good alternative to treat chronic wounds in JEB.Keywords: revertant mosaicism, silver-sulfadiazine, plastic wrap, chronic wound, junctional epidermolysis bullosa more...
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- 2022
Catalog
3. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
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Christine Bodemer, Jouni Uitto, Maria C. Bolling, Giovanna Zambruno, Cristina Has, Anna E. Martinez, Adrian Heagerty, Dedee F. Murrell, John A. McGrath, Jemima E. Mellerio, Katsuto Tamai, M.P. Marinkovich, Johann W. Bauer, Francis Palisson, Celia Moss, Jo-David Fine, David T. Woodley, Anja Diem, Agnes Schwieger-Briel, Eli Sprecher, Leena Bruckner-Tuderman, and Alain Hovnanian more...
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medicine.medical_specialty ,VII COLLAGEN ,Consensus ,Classification scheme ,Dermatology ,Kindler syndrome ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Skin fragility ,CYTOPLASMIC DOMAIN ,Blister ,Disease severity ,Skin blistering ,medicine ,COL7A1 ,Humans ,KINDLER-SYNDROME ,Genetic Association Studies ,Skin ,GLYCINE SUBSTITUTION ,integumentary system ,business.industry ,Inherited epidermolysis bullosa ,REVERTANT MOSAICISM ,medicine.disease ,Natural history ,DISEASE SEVERITY ,EXTRACUTANEOUS MANIFESTATIONS ,Epidermolysis bullosa ,business ,Epidermolysis Bullosa ,STEM-CELLS ,SPLICE-SITE MUTATION - Abstract
Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic?. Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add?. We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype–phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603. more...
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- 2020
4. Long-term follow-up of patients with recessive dystrophic epidermolysis bullosa in the Netherlands
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Hendri H. Pas, Robert M.W. Hofstra, Miranda Nijenhuis, Peter C. van den Akker, Marcel F. Jonkman, Hans Scheffer, Anthonie J. van Essen, Rowdy Meijer, Gonnie Meijer, Marian M.J. Kraak, and Translational Immunology Groningen (TRIGR) more...
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Male ,Pathology ,Recessive dystrophic epidermolysis bullosa ,Neuroinformatics [DCN 3] ,medicine.disease_cause ,Biochemistry ,DOMAIN ,Genotype ,COL7A1 ,Child ,Netherlands ,Mutation ,MESSENGER-RNA DECAY ,Exons ,REVERTANT MOSAICISM ,Middle Aged ,Phenotype ,ANCHORING FIBRILS ,Epidermolysis Bullosa Dystrophica ,Pedigree ,NONSENSE ,Child, Preschool ,Type VII collagen ,DISEASE SEVERITY ,Female ,Mechanobullous skin disease ,Adult ,medicine.medical_specialty ,Collagen Type VII ,Adolescent ,Genes, Recessive ,Phenotype-genotype correlations ,Dermatology ,Biology ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Young Adult ,COL7A1 MUTATION ,Microscopy, Electron, Transmission ,Anchoring fibrils ,VII COLLAGEN GENE ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Aged ,EXONIC SPLICING ENHANCERS ,Infant ,Immunostaining ,SKIN ,Follow-Up Studies - Abstract
Background: The current classification of recessive dystrophic epidermolysis bullosa (RDEB) comprises two major subtypes: 'severe generalized RDEB'(RDEB-sev gen) with early-onset, extensive, generalized blistering and scarring, complete absence of type VII Collagen, and bi-allelic COL7A1 null mutations; milder 'generalized other RDEB' (RDEB-O) with reduced-to-normal type VII Collagen expression, and non-null genotypes.Objective: To search for previously unrecognized phenotype-genotype correlations in 33 Dutch RDEB families.Methods: We analyzed extensive clinical follow-up data, available for all patients up to 19 years, detailed type VII Collagen immunostaining and genotypes, and correlated clinical phenotype to molecular phenotype and genotype.Results: We identified 20 novel COL7A1 mutations. In 14 of 15 RDEB-sev gen patients type VII Collagen was completely absent, one had strongly reduced type VII Collagen, and all carried bi-allelic null mutations. Five of 11 RDEB-O patients developed pseudosyndactyly of the fingers preceded by skin atrophy and flexion contractures later in childhood and adolescence. All five had esophageal involvement and growth retardation. Type VII collagen immunostaining ranged from strongly reduced to slightly reduced in RDEB-O patients with pseudosyndactyly, whereas RDEB-O patients without pseudosyndactyly had slightly reduced to normal type VII Collagen staining. There was no difference in genotypes between both groups, although we unexpectedly found bi-allelic null mutations in two of five RDEB-O patients with pseudosyndactyly.Conclusion: Pseudosyndactyly occurs in approximately half of RDEB-O patients when type VII Collagen is strongly reduced. The prognosis in RDEB cannot always be simply predicted from the COL7A1 genotype. (C) 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. more...
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- 2009
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5. Adhesive stripping to remove epidermis in junctional epidermolysis bullosa for revertant cell therapy
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Anna M.G. Pasmooij, A. Gostynski, F. C. L. Deviaene, Hendri H. Pas, M. F. Jonkman, and Translational Immunology Groningen (TRIGR)
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medicine.medical_specialty ,Pathology ,Cell Transplantation ,Cosmetic Techniques ,MOSAICISM ,Dermatology ,Junctional epidermolysis bullosa (medicine) ,Cell therapy ,Cell Adhesion ,revertant cell therapy ,medicine ,Humans ,type XVII collagen ,revertant mosaicism ,Wound Healing ,Tissue Scaffolds ,integumentary system ,TRANSPLANTATION ,business.industry ,medicine.disease ,Lamina lucida ,Transplantation ,medicine.anatomical_structure ,Female ,Tissue Adhesives ,Lamina densa ,Epidermolysis bullosa ,Epidermis ,Epidermolysis Bullosa, Junctional ,business ,Ex vivo - Abstract
BackgroundReplacing mutant skin in epidermolysis bullosa (EB) by epithelial sheets of transduced autologous keratinocytes is the essential surgical step of ex vivo gene therapy. The same applies for revertant cell therapy in which epithelial sheets of revertant autologous keratinocytes are used. Revertant cells can be found in patches of normal skin in patients with junctional EB (JEB) due to revertant mosaicism caused by in vivo reversions.ObjectivesTo develop a technique of adhesive tape stripping as a method for epidermis removal to prepare the acceptor site for revertant cell therapy in a patient with revertant mosaic JEB.MethodsWe performed revertant cell therapy on a patient with mosaic type XVII collagen-deficient non-Herlitz JEB. Skin biopsies were taken from revertant skin on the wrist. Graft production took place on a 3T3-J2 feeder layer resulting in two 6 x 7 cm grafts. An innovative method that uses the pathological plane of least resistance of JEB skin was developed to prepare the acceptor site. A polyacrylate adhesive plaster was placed on the skin and then pulled off with the epidermis.ResultsThe epidermis was easily removed with the plaster. The skin separated at the level of the lamina lucida, leaving a bloodless wound bed of naked lamina densa. Transplantation was successful; the acceptor site healed without scarring. However, blistering could be provoked. The functional repair was not achieved due to the low percentage of revertant cells in the graft.ConclusionsWe conclude that adhesive stripping is a simple, effective and almost painless procedure for removing epidermis for ex vivo cell therapy in EB. more...
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- 2009
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6. Localized and generalized forms of blistering in junctional epidermolysis bullosa due to COL17A1 mutations in the Netherlands
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Hendri H. Pas, G. H. L. Jansen, Anna M.G. Pasmooij, Henny H. Lemmink, M. F. Jonkman, and Translational Immunology Groningen (TRIGR)
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Male ,Pathology ,Turkey ,ECTODOMAIN ,BP180 ,medicine.disease_cause ,Junctional epidermolysis bullosa (medicine) ,Autoantigens ,Blister ,DOMAIN ,Genotype ,Amelogenesis imperfecta ,deletion ,Child ,Netherlands ,Mutation ,medicine.diagnostic_test ,integumentary system ,PEMPHIGOID ANTIGEN ,REVERTANT MOSAICISM ,Middle Aged ,Non-Fibrillar Collagens ,Phenotype ,Child, Preschool ,Female ,SQUAMOUS-CELL CARCINOMA ,Epidermolysis Bullosa, Junctional ,genodermatosis ,Adult ,medicine.medical_specialty ,COL17A1 ,Dermatology ,Immunofluorescence ,COLLAGEN GENE COL17A1 ,Antigen ,medicine ,Humans ,Aged ,GLYCINE SUBSTITUTION ,MILD FORM ,business.industry ,nH-JEB ,Genodermatosis ,medicine.disease ,XVII COLLAGEN ,Microscopy, Fluorescence ,business - Abstract
Background Mutations in the gene COL17A1 coding for type XVII collagen cause non-Herlitz junctional epidermolysis bullosa (nH-JEB).Objectives Here we give an overview of the genotype-phenotype correlation in 12 patients from the Netherlands with type XVII collagen-deficient nH-JEB.Patient and methods Family and personal history and clinical presentation were recorded from each patient, and skin biopsies of intact and bullous skin were taken for immunofluorescence and electron microscopy. The mutations were identified by analysing the patient's DNA isolated from peripheral blood cells.Results DNA analysis identified five novel deletions: 1284delA, 1365delC, 3236delT, 3600-3601delCT and 4425delT. Interestingly, we identified a new patient, homozygous for 4425delT, with an exceptionally mild blistering phenotype. All together, three patients had more localized blistering confined to hands, lower legs and face, absent or very mild nail dystrophy, normal primary hair and sparse secondary hair. Nine patients had generalized blistering, nail dystrophy, sparse primary and absent secondary hair. All 12 patients had amelogenesis imperfecta (enamel pitting). Immunofluorescence (IF) antigen mapping with monoclonal antibodies 1A8C and 1D1 that bind to type XVII collagen, but not to its 97-kDa fragment was completely negative in patients with generalized blistering, whereas reduced in patients with localized blistering.Conclusions Our data reveal that in patients with COL17A1 mutations a localized nH-JEB phenotype can be differentiated from a generalized nH-JEB phenotype by IF antigen mapping. The data are important for genetic counselling at early age when the clinical phenotype is not yet clear. more...
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- 2007
7. Mechanisms of Natural Gene Therapy in Dystrophic Epidermolysis Bullosa
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Marcela Del Rio, Marcel F. Jonkman, Cristina Has, Marta García, Renske Brander, María José Escámez, Rowdy Meijer, Anna M.G. Pasmooij, J. Kohlhase, Hans Scheffer, Dimitra Kiritsi, Leena Bruckner-Tuderman, Peter C. van den Akker, and Translational Immunology Groningen (TRIGR) more...
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Adult ,Mitotic crossover ,Collagen Type VII ,Adolescent ,Genetic enhancement ,Reversion ,Fluorescent Antibody Technique ,Germline mosaicism ,Dermatology ,Biology ,medicine.disease_cause ,Biochemistry ,CLASSIFICATION ,COL17A1 MUTATIONS ,COL7A1 MUTATION ,medicine ,Missense mutation ,Humans ,COHORT ,Child ,Molecular Biology ,EPIDERMIS ,Genetics ,Mutation ,Mosaicism ,Genetic Therapy ,Cell Biology ,REVERTANT MOSAICISM ,Middle Aged ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,medicine.disease ,Phenotype ,Epidermolysis Bullosa Dystrophica ,MITOTIC RECOMBINATION ,Epidermolysis bullosa ,STEM-CELLS - Abstract
Item does not contain fulltext Revertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patient's naturally corrected cells as a source for cell-based therapies. more...
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- 2014
8. Natural Gene Therapy May Occur in All Patients with Generalized Non-Herlitz Junctional Epidermolysis Bullosa with COL17A1 Mutations
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Anna M.G. Pasmooij, Marcel F. Jonkman, Miranda Nijenhuis, Renske Brander, and Translational Immunology Groningen (TRIGR)
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Adult ,Male ,DNA Repair ,DNA repair ,Somatic cell ,Genetic enhancement ,Remission, Spontaneous ,RECOMBINATION ,Locus (genetics) ,Dermatology ,Biology ,Biochemistry ,Autoantigens ,Exon ,Germline mutation ,INDEL Mutation ,SIMPLEX ,LOCUS ,Humans ,Child ,Gene ,Molecular Biology ,Germ-Line Mutation ,Aged ,Genetics ,MILD FORM ,integumentary system ,Mosaicism ,Cell Biology ,Genetic Therapy ,Sequence Analysis, DNA ,REVERTANT MOSAICISM ,Middle Aged ,Non-Fibrillar Collagens ,REVERSION ,Molecular biology ,XVII COLLAGEN ,Female ,AUTOANTIGEN ,Epidermolysis Bullosa ,MESSENGER-RNA ,STEM-CELLS - Abstract
Mutations in the type XVII collagen gene (COL17A1) result in the blistering disorder non-Herlitz junctional epidermolysis bullosa (JEB-nH). The incidence of revertant mosaicism, also called "natural gene therapy", was identified in a cohort of 14 patients with JEB-nH caused by COL17A1 mutations in the Netherlands. Five different in vivo reversions, all correcting the germ-line COL17A1 mutation c.2237delG in exon 30, were found in four mosaic JEB-nH patients. The correcting DNA changes involved a wide variety of somatic mutations, from which an indel mutation (c.2228-101_2263 + 70delins15) and a large deletion of 2,165 base pairs (c.2227 + 153_2336-318del) have not been previously observed in patients with revertant mosaicism. Our results show that there is no preference for a repair mechanism. Moreover, revertant mosaicism was confirmed on a DNA level in 6 out of 10 generalized JEB-nH patients. Further, photo-material and clinical history of the other four generalized JEB-nH patients demonstrated that each patient has revertant skin patches. In contrast, revertant mosaicism was not detected in the four localized JEB-nH patients. The fact that so many, if not all, generalized JEB-nH COL17A1 patients have revertant patches offers opportunities for cell therapies in which the patient's own naturally corrected cells are used as a source. more...
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- 2012
9. Natural gene therapy in dystrophic epidermolysis bullosa
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Gonnie Meijer, Peter C. van den Akker, Marcel F. Jonkman, Anna M.G. Pasmooij, Robert M.W. Hofstra, Miranda Nijenhuis, and Translational Immunology Groningen (TRIGR)
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Adult ,Male ,Pathology ,medicine.medical_specialty ,VII COLLAGEN ,Collagen Type VII ,Nonsense mutation ,DNA Mutational Analysis ,Dermatology ,medicine.disease_cause ,PATIENT ,Young Adult ,Germline mutation ,SIMPLEX ,medicine ,Humans ,EPIDERMIS ,Mutation ,medicine.diagnostic_test ,integumentary system ,business.industry ,MUTATIONS ,TRANSPLANTATION ,Mosaicism ,Homozygote ,Epidermolysis bullosa dystrophica ,General Medicine ,REVERTANT MOSAICISM ,medicine.disease ,REVERSION ,Skin patch ,Epidermolysis Bullosa Dystrophica ,Transplantation ,DOMINANT ,Codon, Nonsense ,Skin biopsy ,Epidermolysis bullosa ,business ,STEM-CELLS - Abstract
Background: Dystrophic epidermolysis bullosa is a genetic blistering disorder caused by mutations in the type VII collagen gene, COL7A1. In revertant mosaicism, germline mutations are corrected by somatic events resulting in a mosaic disease distribution. This "natural gene therapy" phenomenon long has been recognized in other forms of epidermolysis bullosa but only recently in dystrophic epidermolysis bullosa.Observations: We describe a 21-year-old man with recessive dystrophic epidermolysis bullosa carrying the homozygous c.6508C>T (p.Gln2170X) nonsense mutation who reported an unaffected skin patch on his neck where blisters never had occurred. Immunofluorescent type VII collagen staining was normal in 80% of the unaffected skin biopsy; however, it was strongly reduced in the affected skin. In the unaffected skin, the somatic nucleotide substitution c.6510G>T reverted line nonsense codon to tyrosine (p.Gln21.70Tyr), thereby restoring functional protein production.Conclusions: Revertant mosaicism is considered rare in recessive dystrophic epidermolysis bullosa. However, it might be more common than previously anticipated because our patient is the third in whom revertant mosaicism was identified in a short period of time. The correction mechanism is different than that previously reported. Systematic examination of patients with recessive dystrophic epidermolysis bullosa, therefore, will likely reveal more patients with revertant patches. This is important because the natural gene therapy phenomenon may provide opportunities for revertant cell therapy. more...
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- 2011
10. Dystrophic epidermolysis bullosa: a review
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Satoru Shinkuma
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revertant mosaicism ,Pathology ,medicine.medical_specialty ,treatment ,medicine.diagnostic_test ,business.industry ,subtypes ,Genetic enhancement ,Mucocutaneous zone ,Review ,Dermatology ,Disease ,Immunofluorescence ,Malignancy ,medicine.disease ,gene therapy ,Dystrophic epidermolysis bullosa ,type VII collagen ,Type VII collagen ,medicine ,Lamina densa ,business ,anchoring fibril - Abstract
Dystrophic epidermolysis bullosa is a rare inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. The deficiency and/or dysfunction of type VII collagen leads to subepidermal blistering immediately below the lamina densa, resulting in mucocutaneous fragility and disease complications such as intractable ulcers, extensive scarring, malnutrition, and malignancy. The disease is usually diagnosed by immunofluorescence mapping and/or transmission electron microscopy and subsequently subclassified into one of 14 subtypes. This review provides practical knowledge on the disease, including new therapeutic strategies. more...
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- 2015
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