Reduced expression of the epithelial adhesion ligand laminin 5 in the skincauses intradermal tissue separation

Laminin 5, the major keratinocyte adhesion ligand, is found in the lamina l ucida subregion of the epidermal basement membrane of the skin, where it co localizes with the anchoring filaments. Mutations in the genes encoding lam inin 5 cause junctional epidermolysis bullosa, an inherited skin blistering disease characterized by abnormal hemidesmosomes and cleavage of the lamin a lucida leading to epidermal detachment. In this work we describe the gene tic basis of a new subtype of lethal inherited epidermolysis bullosa associ ated with reduced skin reactivity to laminin 5, presence of mature hemidesm osomes, and intradermal cleavage of the skin. The epidermolysis bullosa pat ients were heterozygous for a nonsense mutation (Q896X) and a splice site m utation (764-10T -->G) in the gene (LAMC2) for the gamma2 chain of laminin 5. The nonsense mutation causes accelerated decay of the corresponding mRNA , while the splice site mutation results in maturation of a cryptic wild-ty pe gamma2 mRNA leading to reduced expression of wild-type laminin 5. In vit ro studies using the probands' keratinocytes showed that secretion of reduc ed amounts of functional laminin 5 in the patient, although permitting form ation of hemidesmosomes, fail to restore efficient cell adhesion. Our resul ts provide the first evidence that laminin 5 contributes to the firm adhesi on of the epithelial basement membrane to the underlying stroma, They also show that a low expression level of laminin 5 induces assembly of mature he midesmosomes in vivo but fails to assure a stable cohesion of the dermal-ep idermal junction.