Human Molecular Genetics, Vol 8, 2097-2105, Copyright © 1999 by Oxford University Press
S Chavanas, Y Gache, J Vailly, J Kanitakis, L Pulkkinen, J Uitto, J Ortonne and G Meneguzzi
A general improvement with ageing has been reported in a few cases of
epidermolysis bullosa with pyloric atresia (PA-JEB), an autosomal recessive
skin disease characterized by extensive disadhesion of epithelia. In a
patient who improved from severe to mild PA-JEB, a search for mutations in
the integrin beta4 gene (IGTB4) detected heterozygosity for a novel base
substitution 3986-19T-->A in the putative branchpoint sequence of intron
31, and a point mutation 3802+1G-->A in the donor splice site of intron
30 previously associated with severe PA-JEB. Analysis of mRNA showed that
the intronic mutation prevents legitimate splicing of the beta4 pre-mRNA.
Functional splicing can be restored in vitro by seeding the proband's
keratinocytes on feeders of irradiated fibroblasts. Study of mRNA in
wild-type keratinocytes transfected with IGTB4 minigenes containing intron
31 with or without mutation 3986-19T-->A, confirmed the causative role
of the intronic mutation in PA-JEB, and highlighted the influence of
feeders on the maturation process of the mutated beta4 pre-mRNA. Our
results show that in a context of overall reduction of the beta4 mRNA
levels, activation of the legitimate splice site in the aberrant beta4
pre-mRNA underlies the transient severity of the condition. The results
also point to the relevance which the interaction between epithelial and
stromal cells may have in modulating expression of integrin receptors.
ARTICLES
Splicing modulation of integrin beta4 pre-mRNA carrying a branch point mutation underlies epidermolysis bullosa with pyloric atresia undergoing spontaneous amelioration with ageing
U385 INSERM, Faculte de Medecine, Avenue de Valombrose, 06107 Nice Cedex 2, France,
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