Rapid Decay of α6 Integrin Caused by a Mis-Sense Mutation in the Propeller Domain Results in Severe Junctional Epidermolysis Bullosa with Pyloric Atresia

Genetic mutations in α6β4 integrin cause junctional epidermolysis bullosa with pyloric atresia, a genodermatosis characterized by blistering of the skin and pyloric occlusion. The lethal form of junctional epidermolysis bullosa with pyloric atresia has been mainly associated with the presence of premature termination codons in the mRNA encoding either the α6 or β4 subunit causing rapid decay of the mutated transcript and absence of α6β4 integrin. In this study, we disclose the genetic background of lethal junctional epidermolysis bullosa with pyloric atresia in a patient presenting absent expression of α6 integrin despite normal steady-state level of the α6β4 mRNA. Screening for mutation in the α6 gene detected a homozygous base pair substitution (286 C-to-T), which results in the substitution of a serine with a leucine residue (S47L). The amino acid substitution S47L localizes in the first β-strand of the seven-bladed β-propeller structure of the extracellular head of α6 integrin, and triggers a rapid proteolysis of the aberrant polypeptides involving the lysosomal degradation pathway. This study provides new insight into the pathogenic effect of a mis-sense mutation affecting a functional domain of a protein, and identifies a critical peptide sequence of the β-propeller domain conserved among the α integrin cell receptors.