title: Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging.
abstract: 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 beta3 mRNAs underwent rapid decay shortly after birth, and that illegitimate splicing of the mRNA carrying mutation 1587delAG generated a new internally shortened beta3 transcript with advancing age. Our genetic and biochemical data show that (i) the illegitimate splicing of the beta3 pre-mRNA results in synthesis and secretion of a laminin 5 heterotrimer with an internally deleted beta3 polypeptide, (ii) expression of the mutated beta3 polypeptide is up-regulated in the basal keratinocytes with high proliferative potential, (iii) 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 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.
authors.affiliation: INSERM U385, Faculté de Médecine, 06107 Nice Cedex 2, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Gache
authors.forename: M
authors.initials: M
authors.lastname: Allegra
authors.forename: C
authors.initials: C
authors.lastname: Bodemer
authors.forename: A
authors.initials: A
authors.lastname: Pisani-Spadafora
authors.forename: Y
authors.initials: Y
authors.lastname: de Prost
authors.forename: J P
authors.initials: JP
authors.lastname: Ortonne
authors.forename: G
authors.initials: G
authors.lastname: Meneguzzi
mesh_terms: D000367:Age Factors; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D018389:Codon, Nonsense; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D016109:Epidermolysis Bullosa, Junctional / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D005260:Female; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007797:Laminin / Q000235:genetics; D008297:Male; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D012720:Severity of Illness Index; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D018389:Codon, Nonsense; D004247:DNA; D007797:Laminin; D012333:RNA, Messenger; D000097794:Kalinin