Digenic junctional epidermolysis bullosa: Mutations in COL17A1 and LAMB3 genes

Junctional epidermolysis bullosa (JEB), a genetically heterogeneous group o f blistering skin diseases, can be caused by mutations in the genes encodin g laminin 5 or collagen XVII, which are components of the hemidesmosome-anc horing filament complex in the skin. Here, a family with severe nonlethal J EB and with mutations in genes for both proteins was identified. The index patient was compound heterozygous for the COL17A1 mutations L855X and R1226 X and was heterozygous for the LAMB3 mutation R635X. As a consequence, two functionally related proteins were affected. Absence of collagen XVII and a ttenuated laminin 5 expression resulted in rudimentary hemidesmosome struct ure and separation of the epidermis from the basement membrane, with severe skin blistering as the clinical manifestation. In contrast, single heteroz ygotes carrying either (1) one or the other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and a LAMB3 null allele did not hav e a pathological skin phenotype. These observations indicate that the known allelic heterogeneity in JEB is further complicated by interactions betwee n unlinked mutations. They also demonstrate that identification of one muta tion in one gene is not sufficient for determination of the genetic basis o f JEB in a given family.