Novel ITGB4 mutations in a patient with junctional epidermolysis bullosa-pyloric atresia syndrome and altered basement membrane zone immunofluorescence for the alpha6beta4 integrin.

Immunofluorescence studies of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) have suggested abnormalities in the expression of the alpha6 beta4 integrin, an integral component of hemidesmosomes. In this study, we examined a family with two affected individuals with JEB-PA for mutations in the ITGA6 and ITGB4 genes which encode the alpha6 and beta4 integrin polypeptides, respectively. Mutation detection strategy based on PCR amplification of genomic DNA, followed by heteroduplex analysis and direct nucleotide sequencing, did not reveal sequence variants in ITGA6. Putative pathogenic mutations, however, were identified in both ITGB4 alleles. Specifically, the proband was a compound heterozygote for a 1-bp maternal deletion, 3434delT, and an 8-bp paternal deletion, 4050de18. Both mutations result in a frameshift and premature termination codon downstream from the deletion. At the protein level, immunofluorescence of the skin of the proband revealed negative staining for the integrin alpha6 and markedly reduced staining for the beta4 subunit. Thus, the results support the notion of close association of the alpha6 beta4 integrin subunits and further attest to the critical role of this integrin in providing physiologic stability to the dermal-epidermal junction.