Deletion of the cytoplasmatic domain of BP180/collagen XVII causes a phenotype with predominant features of epidermolysis bullosa simplex.

BP180/collagen XVII is a hemidesmosomal transmembrane molecule serving as cell-surface receptor. Mutations in its gene cause junctional epidermolysis bullosa. Here, we report a patient with mutations in the gene for BP180/collagen XVII, COL17A1, but predominant phenotypic features of epidermolysis bullosa simplex. At birth, the proband presented with bullous lesions on the trunk, face, and hands. Ultrastructurally, hemidesmosomes were fairly normal, but the attachment of intermediate filaments with the hemidesmosomal plaques appeared to be impaired. Blister formation demonstrated both intraepidermal and junctional cleavage. Immunofluorescence staining with antibodies to keratins, several hemidesmosomal proteins, and the extracellular domain of BP180/collagen XVII showed normal staining patterns, whereas an antibody against the intracellular domain of BP180/collagen XVII yielded a negative immunofluorescence signal. Analysis of BP180/collagen XVII cDNA revealed a 1172 bp deletion corresponding to an in-frame deletion from Ile-18 to Asn-407 from the intracellular domain of the polypeptide. Mutation analysis of the COL17A1 gene disclosed a paternal nonsense mutation, R1226X, and a large maternal genomic deletion extending from intron 2 to intron 15, but no mutations in basal keratin genes. These findings underline the functional importance of the intracellular BP180/collagen XVII domain for the interaction of hemidesmosomes with keratin intermediate filaments and for the spatial stability of basal keratinocytes, and provide a functional explanation for the epidermolysis-bullosa- simplex-like phenotype. Further, the data demonstrate that defects in a given gene can cause unexpected phenotypes of epidermolysis bullosa categories, depending on the function of the affected protein domain.