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

M. Brendan Shannon, Bruce Patton, Scott J. Harvey, Jeffrey H. Miner

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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 α5 (Lama5), a major tubular and glomeralar 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 (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.

Original languageEnglish (US)
Pages (from-to)1913-1922
Number of pages10
JournalJournal of the American Society of Nephrology
Volume17
Issue number7
DOIs
StatePublished - Jul 2006

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Polycystic Kidney Diseases
Cysts
Mutation
Basement Membrane
Genes
Proteinuria
Extracellular Matrix
Nephrons
Introns
Renal Insufficiency
Exons
Animal Models
Alleles
kalinin
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Nephrology

Cite this

A hypomorphic mutation in the mouse laminin α5 gene causes polycystic kidney disease. / Shannon, M. Brendan; Patton, Bruce; Harvey, Scott J.; Miner, Jeffrey H.

In: Journal of the American Society of Nephrology, Vol. 17, No. 7, 07.2006, p. 1913-1922.

Research output: Contribution to journalArticle

Shannon, M. Brendan ; Patton, Bruce ; Harvey, Scott J. ; Miner, Jeffrey H. / A hypomorphic mutation in the mouse laminin α5 gene causes polycystic kidney disease. In: Journal of the American Society of Nephrology. 2006 ; Vol. 17, No. 7. pp. 1913-1922.
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