A hypomorphic mutation in the mouse laminin α5 gene causes polycystic kidney disease

• Published in: Journal of the American Society of Nephrology 2006-07, Vol.17 (7), p.1913-1922
• Main Authors: BRENDAN SHANNON, M, PATTON, Bruce L, HARVEY, Scott J, MINER, Jeffrey H
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Kidneys; Malformations of the urinary system; Medical sciences; Nephrology. Urinary tract diseases
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2005121298

Extracellular matrix abnormalities have been found in both human and animal models of polycystic kidney disease (PKD). We have produced a new mouse PKD model through insertion of a PGK neo cassette in an intron of the gene encoding laminin α5, a major tubular and glomerular basement membrane component important for glomerulogenesis and ureteric bud branching. Lama5 neo represents a hypomorphic allele due to aberrant splicing. Lama5 neo/neo mice exhibit PKD, proteinuria, and death from renal failure by 4 weeks of age. This contrasts with mice totally lacking laminin α5, which die in utero with multiple developmental defects. At 2 days of age, Lama5 neo/neo mice exhibited mild proteinuria and microscopic cystic transformation. By 2 weeks, cysts were grossly apparent in cortex and medulla, involving both nephron and collecting duct segments. Tubular basement membranes appeared to form normally, and early cyst basement membranes showed normal ultrastructure but developed marked thickening as cysts enlarged. Overall, laminin α5 protein levels were severely reduced due to mRNA frameshift caused by exon skipping. This was accompanied by aberrant accumulation of laminin-332 (α3β3γ2; 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.