Laminin β2 variants associated with isolated nephropathy that impact matrix regulation.

Yamato Kikkawa,Masataka Hisano,Keiichi Takizawa,Yuko Akioka,Keisuke Hamada,Masumi Matsunuma,Haruka Masuda,Taeko Hashimoto,Yutaka Harita,Motoyoshi Nomizu,Kenichiro Miura,Seiya Urae,Jeffrey H Miner,Motoshi Hattori,Yuji Yamada,Helen Liapis

doi:10.1172/jci.insight.145908

Abstract

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.

Highlights

The glomerular filtration barrier allows the efficient flow of water and small molecules while preventing plasma proteins from leaking into the urine
We previously reported a Japanese patient with isolated nephropathy carrying LAMB2 p.R469Q and p.G699R variants [12]
Our whole-exome analyses of the patient and his parents showed that c.1406G>A (p.R469Q) and c.2095G>C (p.G699R) in LAMB2 are derived from his father and mother, respectively

Summary

Introduction

The glomerular filtration barrier allows the efficient flow of water and small molecules while preventing plasma proteins from leaking into the urine. The barrier consists of podocytes, endothelial cells, and the glomerular basement membrane (GBM). Nephrotic syndrome can be caused by dysfunctions of podocytes, endothelial cells, or GBM, indicating that all 3 components are essential for maintaining the glomerular filtration barrier. Mutations in the laminin β2 gene (LAMB2) cause Pierson syndrome, which is characterized by congenital nephrotic syndrome with severe ocular and neuromuscular defects [5]. A patient with Pierson syndrome carrying p.S80R presented with late-onset nephrotic syndrome that was diagnosed when the patient was 6.5 years old [5]. Another missense mutation, p.C321R, is associated with congenital nephrotic syndrome, despite less severe extrarenal defects [5]. Mutations in the LN domain have been implicated in the perturbation of BM formation

Methods

Results

Conclusion