A Homozygous Deletion Mutation in the Gene Encoding the 180-kDa Bullous Pemphigoid Antigen (BPAG2) in a Family with Generalized Atrophic Benign Epidermolysis Bullosa

McGrath, John A.; Darling, Thomas N.; Gatalica, Biljana; Pohla‐Gubo, G.; Hintner, Helmut; Christiano, Angela M.; Yancey, Kim B.; Uitto, Jouni

doi:10.1111/1523-1747.ep12345821

Cited by 63 publications

(41 citation statements)

References 23 publications

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“…In vivo subepidermal blistering is observed when expression of BP180 is reduced or absent because of gene knockout in mice or mutation in humans with generalized atrophic benign epidermolysis bullosa (6,49). Van den Bergh and colleagues (50) demonstrated that in cells that lack other hemidesmosomal components, cell matrix attachment is directly related to the amount of BP180 expression.…”

Section: Discussionmentioning

confidence: 99%

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

Messingham

Srikantha

DeGueme

et al. 2011

The Journal of Immunology

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Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by IgE and IgG class autoantibodies specific for 180-kDa BP Ag 2 (BP180), a protein involved in cell-substrate attachment. Although some direct effects of BP IgG have been observed on keratinocytes, no study to date has examined direct effects of BP IgE. In this study, we use primary cultures of human keratinocytes to demonstrate Ag-specific binding and internalization of BP IgE. Moreover, when BP IgE and BP IgG were compared, both isotypes stimulated FcR- independent production of IL-6 and IL-8, cytokines critical for BP pathology, and elicited changes in culture confluence and viability. We then used a human skin organ culture model to test the direct effects of these Abs on the skin, whereas excluding the immune inflammatory processes that are triggered by these Abs. In these experiments, physiologic concentrations of BP IgE and BP IgG exerted similar effects on human skin by stimulating IL-6 and IL-8 production and decreasing the number of hemidesmosomes localized at the basement membrane zone. We propose that the Ab-mediated loss of hemidesmosomes could weaken attachment of basal keratinocytes to the basement membrane zone of affected skin, thereby contributing to blister formation. In this article, we identify a novel role for IgE class autoantibodies in BP mediated through an interaction with BP180 on the keratinocyte surface. In addition, we provide evidence for an FcR-independent mechanism for both IgE and IgG class autoantibodies that could contribute to BP pathogenesis.

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Section: Discussionmentioning

confidence: 99%

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

Messingham

Srikantha

DeGueme

et al. 2011

The Journal of Immunology

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“…The proband, a 56-year-old woman, is a member of a large Austrian GABEB kindred that includes 5 affected and 5 unaffected siblings in 1 generation, as well as a pedigree that signifies propagation of the mutant allele through at least 6 generations (18,21). All 4 living affected siblings (1 affected having died in infancy because of complications of this inherited blistering disease) are homozygous for a 2-bp deletion in COL17A1, 4003delTC, and show the same homozygous haplotype for 5 intragenic COL17A1 polymorphisms (17,18,22). The proband's skin shows the same extent and character of blistering as that of her affected siblings; i.e., regions of nonfragile skin are not present.…”

Section: Methodsmentioning

confidence: 99%

“…14). In the largest GABEB kindred identified to date, affected individuals are homozygous for a 2-bp deletion, 4003delTC, which results in a frameshift and a premature termination codon (PTC) 86 bp downstream (17,18). This mutation results in nonsense-mediated mRNA decay that abolishes synthesis of type XVII collagen and accounts for the absence of this adhesion molecule in the epidermal BM of these patients (18).…”

Section: Introductionmentioning

confidence: 99%

Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation

Darling

Yee

Bauer³

et al. 1999

J. Clin. Invest.

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“…3 and 4). Most are null mutations resulting in premature termination codons and, subsequently, in nonsense-mediated mRNA decay, whereas some missense mutations and small deletions have been reported (5)(6)(7)(8)(9)(10).…”

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confidence: 99%

C-terminal Truncation Impairs Glycosylation of Transmembrane Collagen XVII and Leads to Intracellular Accumulation

Franzke

Has

Schulte

et al. 2006

Journal of Biological Chemistry

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Collagen XVII, a type II transmembrane protein in hemidesmosomes, is involved in the anchorage of stratified epithelia to the underlying mesenchyme. Its functions are regulated by ectodomain shedding, and its genetic defects lead to epidermal detachment in junctional epidermolysis bullosa (JEB), a heritable skin fragility syndrome, but the molecular disease mechanisms remain elusive. Here we used a spontaneously occurring homozygous COL17A1 deletion mutant in JEB to discern glycosylation of collagen XVII. The mutation truncated the distal ectodomain and positioned the only N-glycosylation site 34 amino acids from the newly formed C terminus, which impaired efficient N-glycosylation. Immunofluorescence staining of authentic JEB keratinocytes and of COS-7 cells transfected with the mutant indicated intracellular accumulation of collagen XVII precursor molecules. Cell surface biotinylation and quantification of ectodomain shedding demonstrated that only about 15% of the truncated collagen XVII reached the cell surface. The cell surface-associated molecules were N-glycosylated in a normal manner, in contrast to the molecules retained within the cells, indicating that N-glycosylation of the ectodomain is required for targeting of collagen XVII to the plasma membrane and that reduced accessibility of the N-glycosylation site negatively regulates this process. Functional consequences of the strong reduction of collagen XVII on the cell surface included scattered deposition of cell adhesion molecule laminin 5 into the extracellular environment and, as a consequence of faulty collagen XVII-laminin ligand interactions, aberrant motility of the mutant cells.Collagen XVII belongs to the family of collagenous transmembrane proteins, which function both as cell membrane receptors and as extracellular matrix components and are involved in a broad spectrum of biological events, ranging from cell adhesion to host defense (1). The group members typically are trimers of identical polypeptides, ␣-chains, which contain an N-terminal intracellular domain, a single transmembrane stretch, and a large extracellular C terminus with one or more collagenous subdomains, i.e. a structure characteristic of type II transmembrane proteins. The ectodomain is shed from the cell surface by metalloproteinases of the ADAM (a disintegrin and metalloprotease domain) family to yield a shorter form of the molecule, which remains stable in the extracellular space after the release (2). As a component of the hemidesmosomes, collagen XVII is involved in the anchorage of stratified epithelia in the skin, the mucous membranes, or the eye to the underlying mesenchyme.Mutations in the collagen XVII gene, COL17A, cause JEB, a genodermatosis characterized by mechanically induced detachment of the epidermis from the dermis. To date, over 30 different COL17A1 mutations have been reported (Human Gene Mutation Database, Cardiff University; Refs. 3 and 4). Most are null mutations resulting in premature termination codons and, subsequently, in nonsense-mediated mRNA d...

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A Homozygous Deletion Mutation in the Gene Encoding the 180-kDa Bullous Pemphigoid Antigen (BPAG2) in a Family with Generalized Atrophic Benign Epidermolysis Bullosa

Cited by 63 publications

References 23 publications

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation

C-terminal Truncation Impairs Glycosylation of Transmembrane Collagen XVII and Leads to Intracellular Accumulation

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