Novel mutations in the LAMB3 gene shared by two Japanese unrelated families with Herlitz junctional epidermolysis bullosa, and their application for prenatal testing.

The LAMB3 gene encoding the beta3 chain of laminin 5 is a candidate gene for mutations in the autosomal recessive blistering skin disorder, junctional epidermolysis bullosa. In this study, we performed genetic analyses in two unrelated Japanese families with Herlitz junctional epidermolysis bullosa and identified two novel nonsense mutations in the LAMB3 gene. One of them, Q166X (CAG --> TAG), was found in the maternal allele of family 1 and the paternal allele of family 2. Conversely, the other mutation, W610X (TGG --> TGA), was found in the paternal allele of family 1 and the maternal allele of family 2. Thus, probands of both families were compound heterozygotes for these nonsense mutations. Haplotype analyses with intragenic LAMB3 polymorphisms suggested that both mutations had arisen independently in these two families. Both mutations create a premature translation termination codon predicting truncated beta3 chains that lead to absent expression of laminin 5 in the epidermal basement membrane zone. Based on these results, DNA-based prenatal diagnosis was performed by chorionic villus sampling for subsequent pregnancies in both families. Both fetuses were found to be heterozygous carriers of the W610X mutation together with a normal LAMB3 allele, indicating that they were phenotypically unaffected. These findings expand the repertoire of LAMB3 mutations in junctional epidermolysis bullosa, and emphasize the notion that premature termination codons in both alleles of the laminin 5 genes result in Herlitz junctional epidermolysis bullosa.