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Extracellular matrix abnormalities have been found in both human and animal models of polycystic kidney disease (PKD). A new mouse PKD model has been produced through insertion of a PGKneo cassette in an intron of the gene that encodes laminin alpha5 (Lama5), a major tubular and glomerular basement membrane component that is important for glomerulogenesis and ureteric bud branching. Lama5neo represents a hypomorphic allele as a result of aberrant splicing. Lama5neo/neo mice exhibit PKD, proteinuria, and death from renal failure by 4 wk of age. This contrasts with mice that totally lack Lama5, which die in utero with multiple developmental defects. At 2 d of age, Lama5neo/neo mice exhibited mild proteinuria and microscopic cystic transformation. By 2 wk, cysts were grossly apparent in cortex and medulla, involving both nephron and collecting duct segments. Tubular basement membranes seemed to form normally, and early cyst basement membranes showed normal ultrastructure but developed marked thickening as cysts enlarged. Overall, Lama5 protein levels were severely reduced as a result of mRNA frameshift caused by exon skipping. This was accompanied by aberrant accumulation of laminin-332 (alpha3beta3gamma2; formerly called laminin-5) in some cysts, as also observed in human PKD. This constitutes the first evidence that a primary defect in an extracellular matrix component can cause PKD.

A Hypomorphic Mutation in the Mouse Laminin α5 Gene Causes Polycystic Kidney Disease