A homozygous mutation in the integrin alpha 6 gene in junctional epidermolysis bullosa with pyloric atresia

The alpha 6 integrin subunit participates in the formation of both alpha 6 beta 1 and alpha 6 beta 4 laminin receptors, which have been reported to play an important role in cell adhesion and migration and in morphogenesis. In squamous epithelia, the alpha 6 beta 4 heterodimer is the crucial component for the assembly and stability of hemidesmosomes. These anchoring structures are ultrastructurally abnormal in patients affected with junctional epidermolysis bullosa with pyloric atresia (PA-JEB), a recessively inherited blistering disease of skin and mucosae characterized by an altered immunoreactivity with antibodies specific to integrin alpha 6 beta 4. In this report, we describe the first mutation in the alpha 6 integrin gene in a PA-JEB patient presenting with generalized skin blistering, aplasia cutis, and defective expression of integrin alpha 6 beta 4. The mutation (791delC) is a homozygous deletion of a single base (C) leading to a frameshift and a premature termination codon that results in a complete absence of alpha 6 polypeptide. We also describe the DNA-based prenatal exclusion of the disease in this family at risk for recurrence of PA-JEB. Our results demonstrate that, despite the widespread distribution of the alpha 6 integrin subunit, lack of expression of the alpha 6 integrin chain is compatible with fetal development, and results in a phenotype indistinguishable from that caused by mutations in the beta 4 chain, which is expressed in a more limited number of tissues.