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

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. <br></br><br></br> 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. <br></br><br></br> 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 <i>LAMB2</i> are associated with Pierson’s syndrome and mutations in <i>LAMA5</i> have recently been identified in paediatric patients affected by nephrotic syndrome. <br></br><br></br> 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 <i>in vitro</i> 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.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

The Open University

Year dc:date.issued

2018

Author dc:creator

• Falcone, Sara

Language dc:language

en