Genome analysis of collagen disease in MRL/lpr mice: polygenic inheritanceresulting in the complex pathological manifestations

MRL/MpJ-lpr/lpr (MRL/lpr) mice develop collagen disease involving vasculiti s, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjogren's syndrome, respectively. In the previous studies, we observed genetic segregation of these complex pathological manifestations throughou t the genome recombination with a C57B1/6-lpr/lpr or a C3H/HeJ-lpr/lpr (C3H /lpr) strain of mice which rarely develops such lesions, indicating that de velopment of collagen disease is dependent on an MRL host genetic backgroun d. To clarify the mode of inheritance and the gene loci affecting four type s of the lesions in MRL/lpr mice; vasculitis, glomerulonephritis, arthritis and sialoadenitis, a genetic dissection of the lesions was carried out by using MRL/lpr, C3H/lpr, (MRL/lpr x C3H/lpr) Fl intercross, and MRL/lpr x (M RL/lpr x C3H/lpr) F1 backcross mice. Definition of each lesion was performe d by histopathology under light microscopy, and genomic DNA of the backcros s mice were subjected to association studies by chi-square analysis for det ermining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. We obser ved that gene loci recessively associated with each lesion were mapped on d ifferent chromosomal positions. We conclude that each of four types of the lesions in MRL/lpr mice is under the control of different set of genes, sug gesting the complex pathological manifestations of collagen disease result from polygenic inheritance. (C) 2000 Elsevier Science Ireland Ltd. All righ ts reserved.