Genome-Wide Scan in a Novel IgA Nephropathy Model Identifies a Susceptibility Locus on Murine Chromosome 10, in a Region Syntenic to Human IGAN1 on Chromosome 6q22a€“23

摘要

Genetic factors are considered to be involved in the initiation and progression of IgA nephropathy (IgAN) on the basis of racial differences in the prevalence and familial aggregation. The ddY mouse is a spontaneous animal model of human IgAN, with a highly variable incidence and extent of glomerular injury as a result of the heterogeneous background, resembling the human situation. It was hypothesized that susceptibility genes for IgAN can be detected by a genome-wide scan using this model. First, serial renal biopsies were performed at 20, 40, and 60 wk of age in 361 ddY mice. The ddY mice were classified into three groups on the basis of the onset of glomerular injury: Early onset at 20 wk (31.9%), late onset at 40 wk (37.9%), and quiescent even at 60 wk (30.2%). The severity of glomerular lesions in both onset groups correlated with the intensity of glomerular IgA deposition but not with serum IgA level. The genome-wide scan with 270 microsatellite markers identified three chromosomal regions on chromosomes 1, 9, and 10, which were significantly associated with the glomerular injuries. Surprisingly, the peak marker D10MIT86 on chromosome 10 is located on the region syntenic to human 6q22a€“23 with IGAN1, which is the responsible candidate of familial IgAN. In addition, D1MIT16 on chromosome 1 was very closely located at the locus of selectin gene, which is a known candidate of human IgAN. In conclusion, the three-group ddY mouse model can be a useful tool for identifying the susceptibility genes and also to examine their roles in the pathogenesis of IgAN.