NOVEL ITGB4 MUTATIONS IN LETHAL AND NONLETHAL VARIANTS OF EPIDERMOLYSIS-BULLOSA WITH PYLORIC ATRESIA - MISSENSE VERSUS NONSENSE

Epidermolysis bullosa with pyloric atresia (EB-PA), an autosomal reces sive genodermatosis, manifests with neonatal cutaneous blistering asso ciated with congenital pyloric atresia. The disease is frequently leth al, but nonlethal cases have also been reported. Expression of the alp ha 6 beta 4 integrin is altered at the dermal-epidermal basement-membr ane zone; recently, mutations in the corresponding genes (ITGA6 and IT GB4) have been disclosed in a limited number of patients, premature te rmination codons in both alleles being characteristic of lethal varian ts. Zn this study, we have examined the molecular basis of EB-PA In fi ve families, two Of them with lethal and three of them with nonlethal variants of the disease. Mutation analysis disclosed novel lesions in both ITGB4 alleles of each proband. One of the patients with lethal EB -PA was a compound heterozygote for premature termination-codon mutati ons (C738X/4731delCA), whereas the other patient with a lethal variant was homozygous for a missense mutation involving a cysteine residue ( C61Y). The three nonlethal cases had missense mutations in bath allele s (C562R/C562R, R1281W/R252C, and R1281W/R1281W), Immunofluorescence s taining of skin in two of the nonlethal patients and in one of the let hal cases was positive, yet attenuated, for alpha 6 and beta 4 integri ns. These results confirm that ITGB4 mutations underlie EB-PA and show that missense mutations may lead to nonlethal phenotypes.