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 severe blistering disease affecting the skin and mucous membranes, and laminin 5 has been implicated as the candidate gene/protein system for most patients with H-JEB, In this study, we have examined a cohort of 14 families with H-JEB for mutations in the LAMB3 gene, Premature termination codon mutations were delineated in both alleles of each proband in all pedigrees, Interestingly, two recurrent mutations, R42X and R635X, were noted in over 50% of the mutant LAMB3 alleles, These nonsense mutations occurred at CPG dinucleotide sequences, suggesting hypermutability of 5-methylcytosine to thymine. Additional evidence suggested that R42X and R635X represent mutational hotspots, First, the inheritance of R635X in a homozygous individual on two different genetic backgrounds was demonstrated by haplotype analysis. Furthermore, in one family, R42X was shown to be inherited on the maternal allele which lacked this mutation, suggesting that it arose as a result of maternal germline mutation. Elucidation of these two hotspot mutations will facilitate screening of additional JEB patients for the underlying mutations.