Disease relevance of COL17A1

• Cloning of the human type XVII collagen gene (COL17A1), and detection of novel mutations in generalized atrophic benign epidermolysis bullosa [1].
• Three novel homozygous point mutations and a new polymorphism in the COL17A1 gene: relation to biological and clinical phenotypes of junctional epidermolysis bullosa [2].
• Genetic variation in COL17A1 and the development of bullous pemphigoid [3].
• Aberrant expression of a hemidesmosomal protein, bullous pemphigoid antigen 2, in human squamous cell carcinoma [4].
• BACKGROUND: Cicatricial pemphigoid (CP) is an autoimmune subepidermal blistering disease where autoantibodies target various components of the dermal-epidermal junction, including the bullous pemphigoid antigen 180 (BP180) [5].

Psychiatry related information on COL17A1

• We compared brain reward function during withdrawal following an initial exposure to alcohol in alcohol-naïve rats selectively bred for high (HAD1 line) versus low (LAD1 line) voluntary alcohol consumption [6].

High impact information on COL17A1

• Specifically, the maternal allele surrounding the mutation site on COL17A1 (1706delA) showed reversion of the mutation and loss of heterozygosity along a tract of at least 381 bp in revertant keratinocytes derived from clinically unaffected skin patches; the paternal mutation (R1226X) remained present in all cell samples [7].
• We report here that the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene conversion of one of the two mutated COL17A1 alleles [7].
• In an experimental BP model in mice, the subepidermal blistering is mediated by antibodies directed against the hemidesmosomal protein BP180 (collagen XVII, BPAG2), and depends on complement activation and neutrophil infiltration [8].
• Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 and BP230 [9].
• Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1 [10].

Chemical compound and disease context of COL17A1

• In this study, we report a patient with a form of junctional epidermolysis bullosa with skin fragility and dental anomalies who is a compound heterozygote for a novel combination of mutations, ie, a glycine substitution mutation in one allele and an internal duplication in the other allele of COL17A1 [11].
• Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa [12].
• These data show that deletion of the third fibronectin type III repeat in the cytoplasmic domain of integrin beta4, which is thought to interact with BP180/type XVII collagen, is clinically pathogenic and results in a mild phenotype with predominant features of epidermolysis bullosa simplex [13].
• The expression of BP180 has previously been demonstrated to be influenced by both calcium (Ca(2+)) concentration and binding of anti-BP180-antibodies in cultured keratinocytes of the skin squamous cell carcinoma line DJM-1 [14].
• Bullous pemphigoid (BP) and herpes gestationis (HG) are subepidermal blistering diseases associated with an autoimmune response directed against BP180, an epidermal hemidesmosomal glycoprotein [15].

Biological context of COL17A1

• The homozygous nonsense mutations in the COL17A1 gene were consistent with the absence of the collagen from the skin and with the GABEB phenotype, whereas homozygosity for the missense mutation resulted in expression of aberrant collagen XVII and, clinically, in localisata JEB [2].
• All patients carried novel homozygous point mutations (Q1016X, R1226X, and R1303Q) in the COL17A1 gene encoding collagen XVII, a hemidesmosomal transmembrane component; and, therefore, not only GABEB but also the localisata JEB can be a collagen XVII disorder [2].
• We also have developed a strategy to identify mutations in COL17A1 by use of PCR amplification of genomic DNA, using primers placed on the flanking introns [1].
• Most COL17A1 mutations lead to a premature termination codon (PTC), whereas only a few mutations result in amino acid substitutions or deletions [16].
• Five of the six COL17A1 alleles of three patients originating from the eastern part of the Netherlands were identical, as were the haplotypes including flanking markers [17].

Anatomical context of COL17A1

• To test this hypothesis, we studied the behavior of keratinocytes with null mutations in the COL17A1 gene [18].
• In previous studies, mutations in the gene (COL17A1) encoding the type XVII collagen, a transmembrane component of hemidesmosomes, were detected in most patients with GABEB [19].
• Genomic organization of collagenous domains and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2, a novel collagen of stratified squamous epithelium [20].
• The N terminus of the transmembrane protein BP180 interacts with the N-terminal domain of BP230, thereby mediating keratin cytoskeleton anchorage to the cell surface at the site of the hemidesmosome [21].
• A 97 kDa protein (97-LAD), which localizes at the basement membrane zone of normal human skin, is one of the major autoantigens associated with this disease and possesses multiple regions of amino acid identity with the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAG2 [22].

Associations of COL17A1 with chemical compounds

• The patient also has two offspring, both of whom have inherited the glycine substitution mutation, whereas the other COL17A1 allele is normal [11].
• Several mutations in COL17A1 have been described in patients with GABEB, almost all of which result in a PTC [23].
• The tyrosine activation motif located in the connecting segment (CS) of the beta4 cytoplasmic domain was dispensable for HD formation, although it may be involved in the efficient localization of BP180 [24].
• Unexpectedly, this fragment disrupts the distribution of BP180 in transfected cells but has no apparent impact on the organization of endogenous BP230 and alpha6beta4 integrin [21].
• Bullous pemphigoid antigen 180 (BP180, type XVII collagen) is a transmembrane hemidesmosomal glycoprotein of basal keratinocytes that spans the lamina lucida of the dermal-epidermal junction [25].

Regulatory relationships of COL17A1

• These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes [26].

Other interactions of COL17A1

• Unfolding of the cytoplasmic domain may be part of a mechanism by which the interaction of beta4 with other hemidesmosomal components, e.g., BP180, is regulated [24].
• The index patient was compound heterozygous for the COL17A1 mutations L855X and R1226X and was heterozygous for the LAMB3 mutation R635X [27].
• A second bullous pemphigoid antigen of 180 kDa (BP180/BPAG2) is a type II transmembrane component of the hemidesmosome [21].
• The 97 kDa linear IgA bullous dermatosis antigen is not expressed in a patient with generalized atrophic benign epidermolysis bullosa with a novel homozygous G258X mutation in COL17A1 [28].
• CONCLUSIONS: Mutations in the coding sequence of the human collagen XVII (COL17A1) gene are not the cause of CDB2 [29].

Analytical, diagnostic and therapeutic context of COL17A1

• To test its applicability in skin gene therapy, SMaRT was used in the context of the 4003delTC mutation in the collagen XVII gene (COL17A1) causing generalized atrophic benign junctional epidermolysis bullosa [30].
• The immunofluorescence microscopy studies mentioned above directed mutation studies to the COL17A1 gene [23].
• To investigate further the relationship between 97-LAD and BPAG2, immunogold electron microscopy was performed on cryo-ultrathin sections of normal human skin using a series of polyclonal and monoclonal antibodies [22].
• METHODS: Twenty-six consecutive CP sera were analysed by Western blotting using a panel of cell-derived and recombinant proteins covering the entire BP180 molecule [5].
• On sucrose gradient centrifugation, the soluble BP180 demonstrated a value of approximately 7 S, and chemical cross-linking experiments revealed a trimer form [31].

References