ALTERED LAMININ-5 EXPRESSION DUE TO MUTATIONS IN THE GENE ENCODING THE BETA-3 CHAIN (LAMB3) IN GENERALIZED ATROPHIC BENIGN EPIDERMOLYSIS-BULLOSA

The anchoring filament component laminin 5 (kalinin/nicein) is a candi date protein for mutations in some hereditary blistering skin disorder s. In this study, laminin 5 expression was assessed in a family with g eneralized atrophic benign epidermolysis bullosa, a non-lethal variant of the junctional form of epidermolysis bullosa. Immunofluorescence m icroscopy of the skin basement-membrane zone with a monoclonal antibod y (GB3) revealed reduced antilaminin 5 staining compared to normal con trols. The labeling, when examined by immunoelectron microscopy, was p resent within the lower lamina lucida, immediately below the plane of blister formation. Numerous hemidesmosomes and well-formed anchoring f ilaments were seen on transmission electron microscopy. Polymerase cha in reaction amplification of genomic DNA encoding the beta 3 subunit ( LAMB3) of laminin 5, heteroduplex analysis of the polymerase chain rea ction products, and nucleotide sequencing of the heteroduplexes reveal ed two putative mutations within the LAMB3 gene; these consisted of a premature termination codon in exon 3 and a missense mutation in exon 7. Exons 3 and 7 encode part of domain VI of the laminin 5 beta 3 chai n short arm. This globular domain of the protein has been postulated t o have an important function in the interaction of laminin 5 with othe r structural components of the basement membrane zone, such as laminin 6 (K-laminin). Thus the mutations delineated in this family may have a critical pathogenetic significance in reducing adhesion between the epidermis and the dermis.