Abstract
Laminin 5, the major keratinocyte adhesion ligand, is found in the lamina lucida subregion of the epidermal basement membrane of the skin, where it colocalizes with the anchoring filaments. Mutations in the genes encoding laminin 5 cause junctional epidermolysis bullosa, an inherited skin blistering disease characterized by abnormal hemidesmosomes and cleavage of the lamina lucida leading to epidermal detachment. In this work we describe the genetic basis of a new subtype of lethal inherited epidermolysis bullosa associated with reduced skin reactivity to laminin 5, presence of mature hemidesmosomes, and intradermal cleavage of the skin. The epidermolysis bullosa patients were heterozygous for a nonsense mutation (Q896X) and a splice site mutation (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-type gamma2 mRNA leading to reduced expression of wild-type laminin 5. In vitro studies using the probands' keratinocytes showed that secretion of reduced amounts of functional laminin 5 in the patient, although permitting formation of hemidesmosomes, fail to restore efficient cell adhesion. Our results provide the first evidence that laminin 5 contributes to the firm adhesion of the epithelial basement membrane to the underlying stroma. They also show that a low expression level of laminin 5 induces assembly of mature hemidesmosomes in vivo but fails to assure a stable cohesion of the dermal-epidermal junction.
Highlights
Epidermolysis bullosa (EB)1 is a heterogeneous group of inherited diseases characterized by epithelial fragility to mechanical friction resulting in blisters and erosions of the integument
The Intradermal Cleavage of the Dermal-Epidermal Junction Is Associated with a Reduced Immunoreactivity of Laminin 5—The probands presented with the characteristic clinical phenotype of severe EB
In the lesional skin, immunostaining of laminin 5, type IV collagen, laminin 1, and type VII collagen was located at the roof of the blisters (Fig. 3, A–D), which confirmed the sublamina densa severing of the basement membrane
Summary
Epidermolysis bullosa (EB) is a heterogeneous group of inherited diseases characterized by epithelial fragility to mechanical friction resulting in blisters and erosions of the integument. The dermal-epidermal junction is a complex basement membrane (BM) ultrastructurally composed of four compartments: the ventral plasma membrane of the basal keratinocytes and the associated hemidesmosomes; the lamina lucida, which includes the anchoring filaments; the lamina densa; and the upper papillary dermis containing the anchoring fibrils [2]. Tissue cleavage results from mutations in the extracellular adhesion ligand laminin 5 and the two transmembrane components of hemidesmosomes, integrin ␣64 and collagen type XVII. In blistered nH-JEB skin, immunoreactive laminin 5 distributes along the floor of the blister, which indicates interaction of the protein with components of the lamina densa and the papillary dermis. Additional evidence supporting a structural function of laminin 5 in basement membrane stability includes immunochemical data, which suggests that initiation of skin basement membrane formation involves assembly of laminin 5 into laminin complexes and interaction with integrins 1 and 4 [26]. The active role of laminin 5 in structuring of the basement membrane has not been substantiated by direct in vivo observations and remains hypothetical
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