Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome

Mice homozygous for the transgenic insertion in line OVE250 exhibit severe progressive glomerulonephritis. Ultrastructural changes in the glomerular b asement membrane (GBM) at 2 weeks of age resemble those in Alport syndrome. The transgenic insertion site was mapped by FISH to mouse chromosome 1 clo se to Pax3. Genetic and molecular analyses identified a deletion of genomic DNA at the transgene insertion site. Exons 1 through 12 of the collagen IV gene Col4a4 exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted. Transcripts of Col4a3 and Col4a4 are undetecta ble in mutant kidney, and both proteins are missing from the GBM. Persisten t cellular proliferation in mutant kidneys suggests that interaction with t he extracellular matrix may be important for cell maturation. Evolutionaril y conserved sequence elements in the promoter regions of human and mouse Co l4a3 and Col4a4 include a 19-bp element that was tandemly duplicated in the human lineage and a CTC box element common to several genes encoding extra cellular matrix proteins. This new animal model of Alport syndrome, Col4 De lta 3-4, lacks both alpha 3 and alpha 4 chains of collagen IV and exhibits an earlier disease onset than mice lacking alpha 3 only. (C) 1999 Academic Press.