COMPOUND HETEROZYGOSITY FOR MISSENSE (L156P) AND NONSENSE (R554X) MUTATIONS IN THE BETA-4 INTEGRIN GENE (ITGB4) UNDERLIES MILD, NONLETHAL PHENOTYPE OF EPIDERMOLYSIS-BULLOSA WITH PYLORIC ATRESIA

Mutations in the genes encoding the subunit polypeptides of the alpha 6 beta 4 integrin (ITGA6 and ITGB4, respectively) have been previously demonstrated in patients with a lethal form of epidermolysis bullosa with congenital pyloric atresia (OMIM #226730), In this study, we demo nstrate for the first time ITGB4 mutations in nonlethal phenotype of e pidermolysis bullosa with congenital pyloric atresia, Specifically, th e proband was shown to be a compound heterozygote for a missense mutat ion (L156P) and a nonsense mutation (R554X). The leucine substitution by proline was shown to affect a residue, which was precisely conserve d in different human, rodent, and drosophila integrin-beta polypeptide s, and consequently disrupts the alpha-helix formation of the polypept ide segment as determined by Garnier alpha-helicity plot. The nonsense mutation in another allele was accompanied by undetectable levels of the corresponding mRNA transcript, as determined by reverse transcript ion-polymerase chain reaction. The presence of a missense mutation, wh en combined with a premature termination codon mutation, may explain t he milder blistering tendency of the skin in this patient.