The Human 230-kD Bullous Pemphigoid Antigen Gene (BPAG1): Exon-Intron Organization and Identification of Regulatory Tissue Specific Elements in the Promoter Region

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The 230-kD bullous pemphigoid antigen (BPAG1), a hemidesmosomal protein, is encoded by a gene at the human chromosomal locus 6p11-12. We have elucidated the exon-intron organization of the entire human BPAG1 gene, including (approximately) 2.6 kb of 5'-flanking DNA. Seven overlapping genomic clones, spanning (approximately) 20 kb, contained the entire (approximately) 9 kb coding sequence of BPAG1 and consisted of 22 separate exons, which varied from 78 to 2,810 bp in size. The 5' flanking region of DNA, upstream from the ATG initiation codon for translation, was found to contain several putative transcriptional response elements. Most interestingly, two motifs potentially conferring keratinocyte specific expression to the gene were detected. The presence of such elements was suggested by (approximately) 20-fold higher expression of a promoter/chloramphenicol acetyl transferase (CAT) construct in normal human epidermal keratinocytes that express the endogenous gene, as compared to several nonexpressing cell types. Transient transfections with 5'-deletion clones of the promoter/reporter gene (CAT) constructs identified a region containing a putative tissue specific element, KRE2, which also conferred tissue specificity to the expression of the truncated promoter downstream from this element, however, a mutated derivative of KRE2 was not functional. Detailed knowledge of the structure and regulation of the BPAG1 gene will aid in further elucidation of diseases affecting the cutaneous basement membrane zone. (J. Clin. Invest. 1993. 92:814-822.) Key words: hemidesmosomal proteins. keratinocyte specific expression. blistering skin diseases. epidermolysis bullosa

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