A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa

Abstract Laminin-5 is the major adhesion ligand for epithelial cells. Mutations in the genes encoding laminin-5 cause junctional epidermolysis bullosa (JEB), a recessive inherited disease characterized by extensive epithelial–mesenchymal disadhesion. We describe a JEB patient compound heterozygote for two novel mutations in the gene (LAMA3) encoding the laminin α3 chain. The maternal mutation (1644delG) generates mRNA transcripts that undergo nonsense-mediated decay. The paternal mutation results in the Gly1506 → Glu substitution (G1506E) within the C-terminal globular region of the α3 chain (G domain). Mutation G1506E affects the proper folding of the fourth module of the G domain and results in the retention of most of the mutated polypeptide within the endoplasmic reticulum (ER). However, scant amounts of the mutated laminin-5 are secreted, undergo physiologic extracellular maturation, and correctly localize within the cutaneous basement membrane zone in patient’s skin. Our findings represent the first demonstration of an ER-retained mutant laminin-5 leading to a mild JEB phenotype.