Linkage analysis was performed on 420 female animals from a (C57BL/6Slc x SCG/Knj)F2 intercross to identify QTL for renal phenotypes. Parental strain SCG/Knj is derived from BXSB/Mp and MRL/Mp-Faslpr, and spontaneously develops crescentic glomerulonephritis and vascularitis. The Fas-lpr mutation is largely responsible for the disease phenotype but this experiment seeks to identify non-Fas disease-associated loci. 102 polymorphic markers covering 85% of the genome at a 20 cM resolution was used for the genome scan. F2 animals were analyzed by cohorts grouped by Fas genotype status.
On mouse Chromosome 1, two multifunctional loci were identified. Scgq1 influences mainly anti-chromatin antibodies, vasculitis, and crescent formation whereas Scgq2 mainly influences myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) production.
Scgq1 (spontaneous crescentic glomerulonephritis QTL 1) maps to 87.9 cM near D1Mit15 and spans an 18 cM interval between D1Mit14 (81.6 cM) and D1Mit166(100 cM). This locus shows significant linkage to total serum IgG, anti-ssDNA antibodies, and anti-dsDNA antibodies at 12 weeks of age, as well as reduced lifespan (LOD=4.4-6.5; 16%-22% of the variance). Scgq1 also shows significant linkageto serum IgG at 24 weeks of age, anti-chromatin antibodies at 12 weeks of age, glomerulonephritis, vasculitis, and splenomegaly (LOD=3.5-7; 5%-20% of the variance) in a separate cohort. Linkage to crescent formation reached suggestive to significant statistical significance. Suggestive linkage to anti-ssDNA antibodies, anti-dsDNA antibodies, and anti-chromatin antibodies at 24 weeks of age was also detected. Scg/Knj-derived alleles at Scgq1 confer increased disease traits with an additive mode of inheritance. Previously identified renal QTLs mapping near Scgq1 include Sle1 (88 cM), Lbw7 (90 cM), Nba2 (95 cM), and Yaa4 (formerly Bxs3; 100 cM). Potential candidate genes are Fasl (formerly Tnfsf6; 85 cM), Cd247 (formerly Cd3z; 87.2 cM), Fcgr3a (formerly Fcgr3; 92.29 cM),and Fcgr2b (92 cM).
Scgq2 (spontaneous crescentic glomerulonephritis QTL 2) mapped to 63.1 cM near D1Mit191 and spans a 14 cM interval between D1Mit11 (58.7 cM) and D1Mit102 (78 cM). This QTL is next to Scgq1 but is a separate and distinct locus. Scgq2shows significant linkage to total serum IgG, anti-ssDNA antibodies, anti-dsDNA antibodies, and MPO-ANCA at 12 weeks of age (LOD=4.8-6.1; 11%-13% of the variance). Scgq2 also shows significant linkage to splenomegaly in a different cohort (LOD=4.6; 23% of thevariance). Suggestive linkage to glomerulonephritis and reduced lifespan was also detected. SCG/Knj-derived alleles at Scgq2 confer increased disease traits with a recessive mode of inheritance. Linkage to MPO-ANCA at this locus is represented by thesymbol Mancq1 (MPO-ANCA QTL 1). Cd55 (formerly Daf1; 67.6 cM), Daf2 (67.6 cM), and Serpinb2 (61.1 cM) are potential candidate genes for Mancq1.