Junctional epidermolysis bullosis: defects in expression of epiligrin/nicein/kalinin and integrin beta 4 that inhibit hemidesmosome formation.

Junctional epidermolysis bullosis (JEB) is a heterogeneous inherited blistering disorder of human epithelial basement membranes (BMs). Characteristically, the epidermis detaches from the BM between the basal cells and the lamina lucida due to reduced numbers of hemidesmosomes (HDs). Attempts to identify a candidate gene for JEB led to the characterization of nicein, a protein complex in normal BMs that is absent from BMs of patients with JEB gravis. In independent research, two related BM glycoproteins, epiligrin and kalinin, were identified as functional adhesion components of HDs. Epiligrin was characterized as a BM ligand for basal cell adhesion via integrins alpha 3 beta 1 in focal adhesions and alpha 6 beta 4 in HDs. Kalinin was characterized as an adhesive ligand and a component of anchoring filaments. Recent antibody and sequence studies on epiligrin/nicein/kalinin have identified limited homologies with laminin. Ongoing studies in multiple laboratories seek to identify mutations in one or more of the three subunits of epiligrin that are causal in JEB gravis. Consistent with the genetic heterogeneity of JEB, we have identified a patient with a variant form of JEB that is associated with pyloric atresia. This patient has negligible HDs, normal epiligrin, but reduced expression of integrin beta 4. A defect in the beta 4 expression may define a subset of JEB cases that also present with pyloric atresia. These results testify to the dual requirements for epiligrin in the BM and integrin beta 4 in the plasma membrane in regulating function of HDs in epithelium.