Human Molecular Genetics, 2001, Vol. 10, No. 21 2453-2461
© 2001 Oxford University Press
Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging
INSERM U385, Faculté de Médecine, 06107 Nice Cedex 2 and 1Service de Dermatologie, Hôpital Necker, Enfants Malades, 75730 Paris 15, France
Change of the clinical picture with aging is noted in some patients suffering from junctional epidermolysis bullosa (JEB), an inherited blistering disorder caused by extensive disadhesion of the epithelia. We have studied a patient 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 molecules. Genetic analysis of the gene LAMB3 detected compound heterozygosity for the nonsense mutation R635X and a novel 2 bp deletion (1587delAG) resulting in a downstream premature termination codon. RT–PCR amplification of total RNA purified from skin biopsies demonstrated that the mutated ß3 mRNAs underwent rapid decay shortly after birth, and that illegitimate splicing of the mRNA carrying mutation 1587delAG generated a new internally shortened ß3 transcript with advancing age. Our genetic and biochemical data show that (i) the illegitimate splicing of the ß3 pre-mRNA results in synthesis and secretion of a laminin 5 heterotrimer with an internally deleted ß3 polypeptide, (ii) expression of the mutated ß3 polypeptide is up-regulated in the basal keratinocytes with high proliferative potential, (iii) absence of the N-terminal region of the ß3 rod domain II thought to stabilize the tertiary structure of the laminin 5 is not required for the assembly of the protein and (iv) the mutant laminin 5 retains its adhesive potential. Our results demonstrate that mRNA rescue may underlie the evolution of the clinical phenotype in inherited skin conditions.
+ To whom correspondence should be addressed at: INSERM U385, U.F.R de Médecine, Avenue de Valombrose, 06107 Nice cedex 2, France. Tel: +33 493 37 77 79; Fax: +33 493 81 14 04; Email: meneguzz@unice.fr
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