Two forms of hereditary epidermolysis bullosa (EB), recessive dystrophic EB (RDEB) and recessive junctional EB (RJEB), share the features of having the greatest morbidity and mortality of all forms of EB. Patients with RDEB experience severe blistering, mutilating scarring and often succumb to aggressive skin cancers in the second or third decade of life. Patients suffering from RJEB (often called the lethal form of EB) frequently die before the age of four years. Acquired epidermolysis bullosa (EBA), although often less severe, represents a phenotypic copy of RDEB, but one in which autoantibodies directed against the basement membrane zone of the skin are pathophysiologically important. Although the specific genetic abnormality in RDEB is unknown, defective synthesis, secretion, structure or degradation of type VII collagen has been implicated. Additional evidence suggests that overexpression of interstitial collagenase may be the cause of defective anchoring fibrils (type VII collagen) in vivo. In this proposal we shall expand on cDNA clones that we have already developed to candidate proteins of potential importance in these three types of EB. We shall attempt to determine by linkage analysis if either interstitial collagenase or type VII collagen is the genetic basis for RDEB. Immunostaining of the skin in RJEB reveals a marked reduction or absence in certain subunits of a 600 kDa basement membrane zone protein, termed BM- 600/Nicein. We have isolated and sequenced a partial cDNA clone putatively representing one of the subunits of BM-600 and shall use this clone and additional expression cDNA libraries we have developed to isolate additional clones of value in characterizing further the primary structure of BM-600. Here, we shall attempt to define the chromosomal localization of BM-600 and its genetic polymorphisms. We shall attempt to determine by linkage analysis if one or more component of BM-600 is associated with RJEB. Patients with EBA have tissue-bound and plasma antibodies directed against the anchoring fibril complex (type VII collagen). Our goal is to determine if patients with EBA have a predisposition to autoimmunity to type VII collagen by searching for an association with subtypes within the HLA DR and DQ haplotypes and defining the precise mechanisms for development of the autoimmunity.
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