Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging

Change of the clinical picture with aging is noted in some patients sufferi ng from junctional epidermolysis bullosa (JEB), an inherited blistering dis order caused by extensive disadhesion of the epithelia. We have studied a p atient born with severe JEB associated with absent expression of laminin 5. A remarkable reduction of the blistering tendency was observed with aging that correlated with a restored expression of immunoreactive laminin 5 mole cules. Genetic analysis of the gene LAMB3 detected compound heterozygosity for the nonsense mutation R635X and a novel 2 bp deletion (1587delAG) resul ting in a downstream premature termination codon. RT-PCR amplification of t otal RNA purified from skin biopsies demonstrated that the mutated beta3 mR NAs underwent rapid decay shortly after birth, and that illegitimate splici ng of the mRNA carrying mutation 1587delAG generated a new internally short ened beta3 transcript with advancing age. Our genetic and biochemical data show that (i) the illegitimate splicing of the beta3 pre-mRNA results in sy nthesis and secretion of a laminin 5 heterotrimer with an internally delete d beta3 polypeptide, (ii) expression of the mutated beta3 polypeptide is up -regulated in the basal keratinocytes with high proliferative potential, (i ii) absence of the N-terminal region of the beta3 rod domain II thought to stabilize the tertiary structure of the laminin 5 is not required for the a ssembly of the protein and (iv) the mutant laminin 5 retains its adhesive p otential. Our results demonstrate that mRNA rescue may underlie the evoluti on of the clinical phenotype in inherited skin conditions.