Segregation of experimental autoimmune glomerulonephritis as a complex genetic trait and exclusion of Col4a3 as a candidate gene.
Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar-Kyoto (WKY) rats (RT1-l) by immunization with rat glomerular basement membrane (GBM) in adjuvant. The model in this rat strain is characterized by anti-GBM antibody production accompanied by focal necrotizing glomerulonephritis with crescent formation. The main autoantigen in humans and rats has been identified as the non-collagenous domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1). By contrast, Lewis (LEW) rats with the same MHC background (RT1-l), immunized with the same antigen, develop similar levels of circulating anti-GBM antibodies, but no histological evidence of nephritis. In order to investigate the genetic basis of susceptibility to EAG, we examined the response of both F1 (WKY x LEW) and backcross (BC1; WKY x F1) rats to immunization with rat GBM. F1 animals were completely resistant to the development of EAG, while BC1 animals showed a range of responses from severe crescentic glomerulonephritis to no histological evidence of disease. The results indicate that EAG is inherited as a complex trait under the control of WKY genes unlinked to the MHC. cDNA sequence analysis of alpha3(IV)NC1 in the two parental strains was identical, indicating no predicted amino acid sequence variation in the alpha3(IV)NC1 domain between these strains. Radiation hybrid mapping, using two separate PCR amplicons from rat alpha3(IV)NC1, localized rat Col4a3 to a region of chromosome 9. Since Col4a3 (encoding the autoantigen) is a candidate for susceptibility to EAG, we screened the region of rat chromosome 9 where Col4a3 is localized, using polymorphic microsatellite markers in segregating BC1 progeny. No significant linkage was detected. These results exclude Col4a3 as a recessive susceptibility gene for EAG in the BC1 progeny.
Reynolds
John
J
Renal Section, Division of Medicine, MRC Clinical Sciences Centre and Imperial College Genetics and Genomics Research Institute, Imperial College, Hammersmith Hospital, London, UK. john.reynolds@ic.ac.uk
Cook
Paul R
PR
Ryan
James J
JJ
Norsworthy
Penny J
PJ
Glazier
Anne M
AM
Duda
Mark A
MA
Evans
David J
DJ
Aitman
Timothy J
TJ
Pusey
Ccharles D
CD
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D002874:Chromosome Mapping; D020090:Chromosome Segregation; D024141:Collagen Type IV / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005838:Genotype; D005921:Glomerulonephritis / Q000235:genetics*; D008297:Male; D020412:Multifactorial Inheritance; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000235:genetics; D021101:Radiation Hybrid Mapping; D051381:Rats; D011917:Rats, Inbred Lew; D011921:Rats, Inbred WKY
D001324:Autoantigens; D024141:Collagen Type IV; D018076:DNA, Complementary; C057112:type IV collagen alpha3 chain