Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa

The Herlitz type of junctional epidermolysis bullosa (H-JEB) is a severeblistering disease affecting the skin and mucous membranes, and laminin 5has been implicated as the candidate gene/protein system for most patientswith H-JEB. In this study, we have examined a cohort of 14 families withH-JEB for mutations in the LAMB3 gene. Premature termination codonmutations were delineated in both alleles of each proband in all pedigrees.Interestingly, two recurrent mutations, R42X and R635X, were noted in over50% of the mutant LAMB3 alleles. These nonsense mutations occurred at CpGdinucleotide sequences, suggesting hypermutability of 5-methylcytosine tothymine. Additional evidence suggested that R42X and R635X representmutational hotspots. First, the inheritance of R635X in a homozygousindividual on two different genetic backgrounds was demonstrated byhaplotype analysis. Furthermore, in one family, R42X was shown to beinherited on the maternal allele which lacked this mutation, suggestingthat it arose as a result of maternal germline mutation. Elucidation ofthese two hotspot mutations will facilitate screening of additional JEBpatients for the underlying mutations.