Lack of Type VII Collagen in Unaffected Skin of Patients with Severe Recessive Dystrophic Epidermolysis bullosa

Bruckner‐Tuderman, Leena; Rüegger, Silvia; Odermatt, Bernhard; Mitsuhashi, Yoshihiko; Schnyder, U. W.

doi:10.1159/000248673

Cited by 69 publications

(23 citation statements)

References 11 publications

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“…As described in Table II Although linkage between the type VII collagen gene and the RDEB locus does not demonstrate a causal relationship between this candidate gene and the disease phenotype, we observed no obligate recombinants with the type VII collagen gene (three families with slightly negative lod scores all included one parent who was uninformative for linkage to the marker locus). The lack of obligate recombination, together with compelling evidence for abnormal expression of type VII collagen in skin from RDEB patients (13)(14)(15)(16)(17)(18), strongly suggest that type VII collagen is the gene harboring the deleterious mutation in our RDEB families.…”

Section: Discussionmentioning

confidence: 85%

“…Immunolabelling studies using polyclonal ( 15,16) and monoclonal antibodies against type VII collagen epitopes ( 13,14,17) have revealed absent ( 13-16), or weak and discontinuous staining ( 17) along the dermal-epidermal basement membrane zone in skin from these patients. In addition, intracellular retention of type VII collagen epitopes in basal and suprabasal keratinocytes has been described in a patient with generalized RDEB (20).…”

Section: Discussionmentioning

confidence: 91%

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Genetic linkage of recessive dystrophic epidermolysis bullosa to the type VII collagen gene.

Hovnanian¹,

Duquesnoy²,

Blanchet-Bardon³

et al. 1992

J. Clin. Invest.

133

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Generalized mutilating recessive dystrophic epidermolysis bullosa (RDEB) is characterized by extreme skin fragility owing to loss of dermal-epidermal adherence. Immunohistochemical studies have implicated type VII collagen, the major component of anchoring fibrils, in the etiology of RDEB. In this study, we demonstrate genetic linkage of the type VII collagen gene and the generalized mutilating RDEB phenotype. We first identified a Pvull polymorphic site by digestion of an amplified product of the type VII collagen gene, which was shown to reside within the coding region. Genetic linkage analysis between this marker and the RDEB phenotype in 19 affected families which were informative for this polymorphism showed no recombination events, and gave a maximum lod score of 3.97 at a recombination fraction (0) of 0, demonstrating that this DNA region is involved in this form of RDEB. These data provide strong evidence that the type VII collagen gene, which has also been linked with the dominant form of the disease, harbors the mutation(s) causing the generalized mutilating form of RDEB in these families, thus underscoring the major functional importance of type VII collagen in basement membrane zone stability. (J. Clin. Invest. 1992. 90:1032-1036.) Key words: anchoring fibrils * dermal-epidermal junction * polymerase chain reaction * restriction fragment length polymorphisma lod score.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 91%

Genetic linkage of recessive dystrophic epidermolysis bullosa to the type VII collagen gene.

Hovnanian¹,

Duquesnoy²,

Blanchet-Bardon³

et al. 1992

J. Clin. Invest.

133

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“…6 and 7) with mechanically induced blistering and scarring of the skin. In the most severe forms of the disease, both collagen VII protein and anchoring fibrils are absent from the skin (8), whereas in milder forms, collagen VII is expressed, but the morphology of the anchoring fibrils may be altered (7,9).…”

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confidence: 99%

Some, but Not All, Glycine Substitution Mutations inCOL7A1 Result in Intracellular Accumulation of Collagen VII, Loss of Anchoring Fibrils, and Skin Blistering

Hammami-Hauasli¹,

Schumann²,

Raghunath³

et al. 1998

Journal of Biological Chemistry

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COL7A1 gene mutations cause dystrophic epidermolysis bullosa, a skin blistering disorder. The phenotypes result from defects of collagen VII, the major component of the anchoring fibrils at the dermo-epidermal junction; however, the molecular mechanisms underlying the phenotypes remain elusive. We investigated naturally occurring COL7A1 mutations and showed that some, but not all, glycine substitutions in collagen VII interfered with biosynthesis of the protein in a dominant-negative manner. Three point mutations in exon 73 caused glycine substitutions G2006D, G2034R, and G2015E in the triple helical domain of collagen VII and interfered with its folding and secretion. Confocal laser scanning studies and semiquantitative immunoblotting determined that dystrophic epidermolysis bullosa keratinocytes retained up to 2.5-fold more procollagen VII within the rough endoplasmic reticulum than controls. Limited proteolytic digestions of mutant procollagen VII produced aberrant fragments and revealed reduced stability of the triple helix. In contrast, the glycine substitution G1519D in another segment of the triple helix affected neither procollagen VII secretion nor anchoring fibril function and remained phenotypically silent. These data demonstrate that collagen VII presents a remarkable exception among collagens in that not all glycine substitutions within the triple helix exert dominant-negative interference and that the biological consequences of the substitutions probably depend on their position within the triple helix.Anchoring fibrils attach the epidermal basement membrane of the skin to the underlying dermal connective tissue (1, 2). They represent polymers of collagen VII, a large homotrimeric protein with a central triple helix and flanking amino-and carboxyl-terminal globular domains. Epidermal keratinocytes synthesize and secrete collagen VII as a triple helical precursor (procollagen VII) into the extracellular matrix. After secretion, procollagen VII undergoes proteolytic trimming to collagen VII (3) and assembles to polymers (1). This is a multistep process during which collagen VII monomers first form disulfidebonded antiparallel dimers and then laterally aggregate into anchoring fibrils, which interact with laminin 5 to secure the dermo-epidermal adhesion (1, 4). Further stabilization of anchoring fibrils and presumably of intermolecular aggregates is achieved through cross-linking by transglutaminase-2 (5). Anchoring fibrils are functionally deficient in hereditary dystrophic epidermolysis bullosa (DEB), 1 a heterogeneous group of bullous skin disorders (for reviews, see Refs. 6 and 7) with mechanically induced blistering and scarring of the skin. In the most severe forms of the disease, both collagen VII protein and anchoring fibrils are absent from the skin (8), whereas in milder forms, collagen VII is expressed, but the morphology of the anchoring fibrils may be altered (7, 9).Mutations in COL7A1 encoding collagen VII have been disclosed in both recessive and dominant DEB subtypes (10 -17). In reces...

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“…1A) composed predominantly, if not exclusively, of type VII collagen (18). The pathogenic role of AFs in stabilizing the BMZ has been confirmed by EM observations of them being abnormal, diminished or absent, and by the immunohistochemical finding that type VII collagen is reduced or absent in the group of inherited skin diseases collectively known as dystrophic EB (19)(20)(21)(22). All forms of dystrophic EB were recently found to be directly caused by mutations in the type VII collagen gene (COL7A1) (23)(24)(25)(26).…”

Section: I) Anchoring Fibrils (Afs) Originate and Terminate In The Lamentioning

confidence: 90%

New insights into the immunoultrastructural organization of cutaneous basement membrane zone molecules

Shimizu

1998

Experimental Dermatology

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The epidermal basement membrane zone (BMZ) is composed of various molecules, each of which plays an important role in dermoepidermal adhesion. Genetic abnormality of certain BMZ molecules leads to an inherited group of skin diseases collectively referred to as epidermolysis bullosa, whose hallmark is skin fragility of varying degrees. Furthermore, development of autoantibodies to certain BMZ molecules leads to the onset of a number of acquired autoimmune blistering diseases in which dermo-epidermal separation occurs, including bullous pemphigoid and epidermolysis bullosa acquisita. The ultrastructural location of each BMZ molecule has been studied using a range of immunoelectron microscopy (immuno-EM) techniques. Recent technical advances in imKey words: immunoelectron microscopymuno-EM and in molecular engineering for production of epitope-speci- to these findings, this review focuses on three major BMZ-related mol-

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Lack of Type VII Collagen in Unaffected Skin of Patients with Severe Recessive Dystrophic Epidermolysis bullosa

Cited by 69 publications

References 11 publications

Genetic linkage of recessive dystrophic epidermolysis bullosa to the type VII collagen gene.

Genetic linkage of recessive dystrophic epidermolysis bullosa to the type VII collagen gene.

Some, but Not All, Glycine Substitution Mutations inCOL7A1 Result in Intracellular Accumulation of Collagen VII, Loss of Anchoring Fibrils, and Skin Blistering

New insights into the immunoultrastructural organization of cutaneous basement membrane zone molecules

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