Basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser syndrome-associated proteins

Dysfunction of the basement membrane protein QBRICK provokes Fraser syndrome, which results in renal dysmorphogenesis, cryptophthalmos, syndactyly, and dystrophic epidermolysis bullosa through unknown mechanisms. Here, we show that integrin alpha 8 beta 1 binding to basement membranes was significantly impaired in Qbrick-null mice. This impaired integrin alpha 8 beta 1 binding was not a direct consequence of the loss of QBRICK, which itself is a ligand of integrin alpha 8 beta 1, because knock-in mice with a mutation in the integrin-binding site of QBRICK developed normally and do not exhibit any defects in integrin alpha 8 beta 1 binding. Instead, the loss of QBRICK significantly diminished the expression of nephronectin, an integrin alpha 8 beta 1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin alpha 8 beta 1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome.