Nephrotic Syndrome and Glomerular Basement Membrane: Genetic Defect of the Laminin α5 Chain

Abstract

Nephrotic syndrome is a heterogeneous group of disorders characterised by renal and extra-renal manifestations. Classic symptoms of nephrotic syndrome include severe proteinuria, hypoalbumiaemia, oedema and hyperlipidaemia. Genetic studies of hereditary forms of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signalling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. The laminin α5 chain is a 404 kDa protein essential for embryonic development and, in association with laminin β2 and laminin γ1, it is a major component of the glomerular basement membrane. Mutations in LAMB2 are associated with Pierson’s syndrome and mutations in LAMA5 have recently been identified in paediatric patients affected by nephrotic syndrome. As part of the MRC Harwell Ageing Screen, a large-scale ENU mutagenesis screen, a novel missense mutation (E884G) was identified in the gene Lama5. Homozygous mice showed a nephrotic phenotype including a severe proteinuria that preceded histological and ultrastructural changes. Further investigation using in vitro studies, extensive proteomics analysis and investigation of integrin activation, revealed a possible impact of the causative mutation on protein folding. Data suggest that changes in protein structure lead to a reduced secretion, integrin β1 activation, and agrin expression ultimately resulting in possible instability of the podocyte actin cytoskeleton.