LAMBS MUTATIONS IN GENERALIZED ATROPHIC BENIGN EPIDERMOLYSIS-BULLOSA - CONSEQUENCES AT THE MESSENGER-RNA AND PROTEIN-LEVELS

Generalized atrophic benign epidermolysis bullosa (GABEB; OMIM no. 226 650) is a rare hemidesmosomal variant of EB, inherited in an autosomal recessive fashion. In previous studies, mutations in the gene (COL17A 1) encoding the type XVII collagen, a transmembrane component of hemid esmosomes, were detected in most patients with GABEB. However, evidenc e for genetic defects in the laminin 5 genes has also been presented. In the present investigation, we examined three patients, representing two families with GABEB, for mutations in the LAMBS gene. Heteroduple x scanning of the gene, followed by direct automated sequencing, revea led that Patient 1 was a compound heterozygote for a missense mutation (C293S) and a premature termination codon-causing mutation (1367delAC ). The latter mutation resulted in accelerated mRNA decay, which rende red the corresponding mRNA transcript undetectable by reverse transcri ptase-PCR. Patients 2 and 3, siblings with slightly different clinical presentations, were homozygous for a G-->A transition affecting the l ast nucleotide of exon 7 (628G-->A). This mutation resulted in amino a cid substitution (E210K), as well as in multiple aberrant splice varia nts affecting exons 6 to 8. These observations expand the repertoire o f LAMBS mutations in nonlethal variants of EB, and they illustrate the consequences of the mutations at the mRNA and protein levels.