Novel and recurrent mutations in the integrin beta 4 subunit gene causing lethal junctional epidermolysis bullosa...

In this study we examined two unrelated patients affected with the lethal variant of junctional epidermolysis bullosa with pyloric atresia (PA-JEB) who were found to carry mutations in the integrin beta4 subunit gene (ITGB4). Although in both patients Northern blot analysis showed only a 50% reduction in the level of ITGB4 transcript, a complete lack (patient 1) or a strong reduction (patient 2) of beta4 immunoreactivity was observed in the skin. Using immunoprecipitation analysis, integrin beta4 could not be visualized in patient 1 cells while a markedly reduced amount (approximately 20%) of normal sized beta4 chains was detected in patient 2. These data suggested the presence of ITGB4 mutations that interfere with both mRNA and protein stability. Using molecular analysis, patient 1 was shown to be a compound heterozygous for a single amino acid deletion (deltaN318) and a not yet identified mutation that induces a very rapid decay of the encoded mRNA transcript. Patient 2 was, instead, a compound heterozygous for a novel 4-bp tandem duplication (4298-4299ins4) and a previously described missense mutation (R252C). Our data support the notion that PA-JEB lethal phenotypes associated with a markedly decreased/absent alpha6beta4 expression can be due not only to the presence of null alleles, but also to specific mutations leading to protein instability and/or altered function.