Reduced expression of the epithelial adhesion ligand laminin 5 in the skin causes intradermal tissue separation.
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.
Spirito
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F
U385 INSERM, Faculté de Médecine, Avenue de Valombrose, 06107 Nice cedex 2, France.
Chavanas
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S
Prost-Squarcioni
C
C
Pulkkinen
L
L
Fraitag
S
S
Bodemer
C
C
Ortonne
J P
JP
Meneguzzi
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G
D016475:3T3 Cells; D017398:Alternative Splicing; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D018389:Codon, Nonsense; D018076:DNA, Complementary / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism*; D013997:Time Factors; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D018389:Codon, Nonsense; D018076:DNA, Complementary; D012333:RNA, Messenger; D000097794:Kalinin