Heterozygous females and hemizygous males for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Immunofluorescence analysis of kidney tissue from mutant male mice does not detect gene product (protein), but in kidney from mutant female mice a mosaic pattern of gene product (protein) is detected (due to X-inactivation). RNase protection assay analysis of kidney tissue from mutant male mice detects a significantly lower level than wildtype. Hemizygous male and heterozygous female mice develop progressive kidney disease. By 7 weeks of age, 97% of mutant male mice and 78% of heterozygous female mice exhibit proteinuria. Histological analysis of kidneys from mutant male mice at 4 weeks of age reveals thickened capillary walls and mesangial hypercellularity. The pathology progresses to interstitial inflammation, glomerular abnormalities, and focal sclerosis. Electron microscopic examination of glomerular basement membrane ultrastructure shows lamellation and splitting abnormalities. Female mice heterozygous for the mutation exhibit similar progressive kidney disease but at later onset than the hemizygous males. These mice do not contain the neo selection cassette. This mutant mouse strain may be useful in studies of X-linked Alport syndrome (XLAS). Homozygous females were found to be viable and fertile in colonies at The Jackson Laboratory, though no phenotype information was collected. (June, 2007)

These targeted knock-in mice develop kidney abnormalities, die prematurely, and serve as a model of human X-linked Alport syndrome.

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