Collagen COL4A3 knockout: A mouse model for autosomal Alport syndrome

Dominic Cosgrove, Daniel T. Meehan, James A. Grunkemeyer, Jody M. Kornak, Robinlyn Sayers, William J. Hunter, Gina C. Samuelson

Research output: Contribution to journalArticle

256 Scopus citations

Abstract

A mouse model for the autosomal form of Alport syndrome was produced. These mice develop a progressive glomerulonephritis with microhematuria and proteinuria, consistent with the human disease. End-stage renal disease develops at ~14 weeks of age. TEM analysis of the glomerular basement membranes (GBM) during development of renal pathology revealed focal multilaminated thickening and thinning beginning in the external capillary loops at 4 weeks and spreading throughout the GBM by 8 weeks. By 14 weeks, half of the glomeruli were fibrotic with collapsed capillaries. Immunofluorescence analysis of the GBM showed the absence of type IV collagen α-3, α-4, and α-5 chains and a persistence of α-1 and α-2 chains (these chains normally localize to the mesangial matrix). Northern blot analysis using probes specific for the collagen chains illustrate the absence of COL4A3 in the knockout, whereas mRNAs for the remaining chains are unchanged. An accumulation of fibronectin, heparan sulfate proteoglycan, laminin-1, and entactin was observed in the GBM of the affected animals. The temporal and spatial pattern of accumulation was consistent with that for thickening of the GBM as observed by TEM. Thus, expression of these basement membrane- associated proteins may be involved in the progression of Alport renal disease pathogenesis. The levels of mRNAs encoding the basement membrane- associated proteins at 7 weeks were unchanged.

Original languageEnglish (US)
Pages (from-to)2981-2992
Number of pages12
JournalGenes and Development
Volume10
Issue number23
DOIs
StatePublished - 1996

Keywords

  • Alport syndrome
  • Basement membrane
  • mouse model

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Cosgrove, D., Meehan, D. T., Grunkemeyer, J. A., Kornak, J. M., Sayers, R., Hunter, W. J., & Samuelson, G. C. (1996). Collagen COL4A3 knockout: A mouse model for autosomal Alport syndrome. Genes and Development, 10(23), 2981-2992. https://doi.org/10.1101/gad.10.23.2981