Genetic dissection of the complex pathological manifestations of collagen disease in MRL/Ipr mice

An MRL strain of mice bearing a Fas-deletion mutant gene, Ipr, MRL/MpJ-Ipr/Ipr (MRL/Ipr) develops collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjogren's syndrome, respectively. Development of such lesions seems dependent on host genetic background since the congenic C3H/HeJ-Ipr/Ipr (CBH/Ipr) mice rarely develop them. To identify the gene loci affecting each lesion, a genetic dissection of these complex pathological manifestations was carried out. First, histopathological features in MRL/Ipr, C3H/Ipr, (MRL/Ipr x C3H/Ipr) F1 intercross, and MRL/Ipr x (MRL/Ipr x C3H/Ipr) F1 backcross mice were analyzed. Genomic DNA of the backcross mice were subjected to association studies by Chi-squared analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. As a result, gene loci recessively associated with each lesion were mapped on different chromosomal positions. We concluded that each of these lesions in MRL/Ipr mice is under the control of a different set of genes, suggesting that the complex pathological manifestations of collagen disease result from polygenic inheritance.