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

Abstract: 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 β4 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 β4 immunoreactivity was observed in the skin. Using immunoprecipitation analysis, integrin β4 could not be visualized in patient 1 cells while a markedly reduced amount (∼20%) of normal sized β4 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 (ΔN318) 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 α6β4 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.