Laminin Beta(2) Variants Associated With Isolated Nephropathy That Impact Matrix Regulation

Mutations in LAMB2, encoding laminin beta(2), cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin beta(2). On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the beta(2) LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin beta(2) secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the beta(2) variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin beta(2) to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the beta(2) variants to other laminins appears to lead to their increased deposition in the GBM. Laminin beta(2) also serves as a potentially novel cell-adhesive ligand for integrin a 4 beta(1.) Our findings define biochemical functions of laminin beta(2) variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.