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 alp ha 6 beta 1 and alpha 6 beta 4 laminin receptors, which have been repo rted to play an important role in cell adhesion and migration and in m orphogenesis. In squamous epithelia, the alpha 6 beta 4 heterodimer is the crucial component for the assembly and stability of hemidesmosome s. These anchoring structures are ultrastructurally abnormal in patien ts affected with junctional epidermolysis bullosa with pyloric atresia (PA-JEB), a recessively inherited blistering disease of skin and muco sae characterized by an altered immunoreactivity with antibodies speci fic 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 w ith generalized skin blistering, aplasia cutis, and defective expressi on 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 polype ptide. We also describe the DNA-based prenatal exclusion of the diseas e in this family at risk for recurrence of PA-JEB. Our results demonst rate that, despite the widespread distribution of the alpha 6 integrin subunit, lack of expression of the alpha 6 integrin chain is compatib le with fetal development, and results in a phenotype indistinguishabl e from that caused by mutations in the beta 4 chain, which is expresse d in a more limited number of tissues.