Anchoring Fibrils and Type VII collagen are Absent From Skin in Severe Recessive Dystrophic Epidermolysis Bullosa

Bruckner‐Tuderman, Leena; Mitsuhashi, Yoshihiko; Schnyder, U. W.; Brückner, Peter

doi:10.1111/1523-1747.ep12277331

Cited by 123 publications

(52 citation statements)

References 28 publications

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“…The secreted protein diffuses into the medium. 5,14 In agreement with the observations on the skin, the fibroblasts of normal littermates remained negative with antibodies to human collagen VII (Figure 4cii).…”

Section: Figure 3 Expression Of Human Col7a1 Transgene (Hc7c61) Produsupporting

confidence: 88%

“…58 The dermis was extracted with a neutral buffer containing 8 m urea, 2% SDS, 0.020 m Tris-HCl, pH 6.8 and a mixture of proteinase inhibitors. 14 The proteins were separated on SDS-PAGE using gels with 4.5-15.0% polyacrylamide gradients and transferred on to nitrocellulose. The samples were subjected to immunoblotting using human-specific collagen VII antibodies and alkaline phosphatase-linked anti-rabbit second antibodies (Sigma, Deisenhofen, Germany).…”

Section: Protein Extraction and Immunoblot Analysesmentioning

confidence: 99%

“…In milder DEB subtypes, collagen VII protein is expressed but the anchoring fibrils are morphologically altered. 3,4,10 In the most severe DEB form, both collagen VII and anchoring fibrils are absent from the skin, [11][12][13][14] and the clinical course of the disease is dramatic with extensive blistering and scarring which leads to fusion of the digits of the hands and feet, so called mitten hands. Therefore, this recessively inherited severe subtype is also called mutilating DEB.…”

Section: Introductionmentioning

confidence: 99%

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Tissue-specific expression and long-term deposition of human collagen VII in the skin of transgenic mice: implications for gene therapy

et al. 2000

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We report the isolation of a cosmid clone containing the entire human COL7A1 gene in one piece. The ability of the genomic sequences within this clone to direct tissue-specific expression of human collagen VII in transgenic mice was tested. The data show that the gene construct is capable of directing expression of collagen VII in the skin of fetal and neonatal transgenic mice. Expression of COL7A1 in these mice was widespread, in a pattern consistent with that found in human tissues and was in parallel with that of the endogenous mouse gene. Immunostaining, using humanspecific antibodies, showed that human collagen VII protein

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Section: Figure 3 Expression Of Human Col7a1 Transgene (Hc7c61) Produsupporting

confidence: 88%

Section: Protein Extraction and Immunoblot Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tissue-specific expression and long-term deposition of human collagen VII in the skin of transgenic mice: implications for gene therapy

et al. 2000

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“…The absence of recombinants between the COL7A1 and EBDD loci and the demonstrated anchoring fibril defects in the affected individuals strongly suggest that COL7A1 harbors the underlying mutation in these families. (4)(5)(6), and the anchoring fibrils and type VII collagen are absent in some cases with severe recessive dystrophic EB (7). Previous cell biological investigations concerning the pathogenesis of recessive dystrophic EB have centered around proteolytic degradation ofthe anchoring fibrils (21).…”

Section: Resultsmentioning

confidence: 99%

Genetic linkage of type VII collagen (COL7A1) to dominant dystrophic epidermolysis bullosa in families with abnormal anchoring fibrils.

Ryynänen¹,

Ryynänen²,

Sollberg³

et al. 1992

J. Clin. Invest.

124

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Epidermolysis bullosa (EB) is a group of genodermatoses characterized by the fragility of skin. Previous studies on the dystrophic (scarring) forms of EB have suggested abnormalities in anchoring fibrils, morphologically recognizable attachment structures that provide stability to the association ofthe cutaneous basement membrane to the underlying dermis. Since type VII collagen is the major component ofthe anchoring fibrils, we examined the genetic linkage of dominant dystrophic EB (EBDD) and the type VII collagen gene (COL7A1) locus, which we have recently mapped to chromosome 3p, in three large kindreds with abnormal anchoring fibrils. Strong genetic linkage of EBDD and COL7A1 loci was demonstrated with the maximum logarithm ofodds (LOD) score of 8.77 ata =0. This linkage was further confirmed with two additional markers in this region of the short arm of chromosome 3, and these analyses allowed further refinement of the map locus of COL7A1. Since there were no recombinants between the COL7A1 and EBDD loci, our findings suggest that type VII collagen is the candidate gene that may harbor the mutations responsible for the EB phenotype in these three families. (J. Clin. Invest. 1992.89:974-980.) Key words: basement membrane zone * bullous dermatosis * genetic skin diseases Introduction Epidermolysis bullosa (EB)' is a heterogenous group of mechano-bullous diseases characterized by easy blistering as a result of minor trauma. EB can be divided into three major categories on the basis of the level of tissue separation within the cutaneous basement membrane zone at the dermal-epidermal junction. In the simplex (nonscarring) forms, the blisters de-

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“…Epitopes recognized by the majority of EBA sera were mapped to the noncollagenous 1 (NC1) domain of type VII collagen (5)(6)(7)(8)(9). The essential role that type VII collagen plays in the biology of the DEJ is exemplified by inherited or targeted disruptions in the gene that encodes it, which yield a phenotype characterized by subepidermal blisters (10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Induction of dermal-epidermal separation in mice by passive transfer of antibodies specific to type VII collagen

Sitaru¹,

Mihai²,

Otto³

et al. 2005

J. Clin. Invest.

225

272

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Epidermolysis bullosa acquisita (EBA) is a subepidermal blistering disorder associated with tissue-bound and circulating autoantibodies specific to type VII collagen, a major constituent of the dermal-epidermal junction. Previous attempts to transfer the disease by injection of patient autoantibodies into mice have been unsuccessful. To study the pathogenic relevance of antibodies specific to type VII collagen in vivo, we generated and characterized rabbit antibodies specific to a murine form of this antigen and passively transferred them into adult nude, BALB/c, and C57BL/6 mice. Immune rabbit IgG bound to the lamina densa of murine skin and immunoblotted type VII collagen. Mice injected with purified IgG specific to type VII collagen, in contrast to control mice, developed subepidermal skin blisters, reproducing the human disease at the clinical, histological, electron microscopical, and immunopathological levels. Titers of rabbit IgG in the serum of mice correlated with the extent of the disease. F(ab′) 2 fragments of rabbit IgG specific to type VII collagen were not pathogenic. When injected into C5-deficient mice, antibodies specific to type VII collagen failed to induce the disease, whereas C5-sufficient mice were susceptible to blister induction. This animal model for EBA should facilitate further dissection of the pathogenesis of this disease and development of new therapeutic strategies.

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Anchoring Fibrils and Type VII collagen are Absent From Skin in Severe Recessive Dystrophic Epidermolysis Bullosa

Cited by 123 publications

References 28 publications

Tissue-specific expression and long-term deposition of human collagen VII in the skin of transgenic mice: implications for gene therapy

Tissue-specific expression and long-term deposition of human collagen VII in the skin of transgenic mice: implications for gene therapy

Genetic linkage of type VII collagen (COL7A1) to dominant dystrophic epidermolysis bullosa in families with abnormal anchoring fibrils.

Induction of dermal-epidermal separation in mice by passive transfer of antibodies specific to type VII collagen

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