Laminin β₂ variants associated with isolated nephropathy that impact matrix regulation

Mutations in LAMB2, encoding laminin β₂, 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 β₂. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β₂ 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 β₂ secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β₂ variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β₂ to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β₂ variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β₂ also serves as a potentially novel cell-adhesive ligand for integrin α₄β₁. Our findings define biochemical functions of laminin β₂ variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.