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Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin  β 2 ( LAMB2 ), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient’s nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a  Col4a3  −/−  mouse model of autosomal recessive Alport syndrome and increased proteinuria in  Col4a5  +/−  females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen  α 3 α 4 α 5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same  COL4  mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.

Pathogenicity of a Human Laminin β2 Mutation Revealed in Models of Alport Syndrome