title: 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 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.
authors.affiliation: Laboratory of Molecular and Cell Biology, IDI-IRCCS, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iacovacci
authors.forename: S
authors.initials: S
authors.lastname: Cicuzza
authors.forename: T
authors.initials: T
authors.lastname: Odorisio
authors.forename: E
authors.initials: E
authors.lastname: Silvestri
authors.forename: H
authors.initials: H
authors.lastname: Kayserili
authors.forename: G
authors.initials: G
authors.lastname: Zambruno
authors.forename: P
authors.initials: P
authors.lastname: Puddu
authors.forename: M
authors.initials: M
authors.lastname: D'Alessio
mesh_terms: D004820:Epidermolysis Bullosa / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D039663:Integrin beta4 / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011708:Pylorus / Q000002:abnormalities*; D012307:Risk Factors
chemical_list: D039663:Integrin beta4