L. Pulkkinen et al., NOVEL ITGB4 MUTATIONS IN LETHAL AND NONLETHAL VARIANTS OF EPIDERMOLYSIS-BULLOSA WITH PYLORIC ATRESIA - MISSENSE VERSUS NONSENSE, American journal of human genetics, 63(5), 1998, pp. 1376-1387
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.