While it is known that the occurrence of lupus nephritis is controlled by multigenes, the role of each susceptibility gene has not been clarified. (NZW × BXSB Fl mice, a model of SLE, are unique, in that they spontaneously develop SLE in association with anti-phospholipid syndrome. The disease appears much earlier and is more severe in males, due to the involvement of a mutant Y chromosome-linked gene
Yaa derived from BXSB. As non - BXSB strains carrying
Yaa do not develop the disease, other disease susceptibility genes are apparently involved. In the present studies, we analyzed the chromosomal positions of BXSB alleles predisposing to lupus nephritis of (NZW × BXSB) Fl mice, by means of a genome-wide analysis with microsatellite-based chromosomal maps using NZW X (NZW × BXSB) Fl backcross mice. Analyses using female backcross mice lacking
Yaa showed that a dominant allele located in the vicinity of the H-2 complex on chromosome 17 determines the trait and that an allele located in the centromeric portion on chromosome 7 modifies to increase the effect. On the other hand, analyses using male backcross mice carrying
Yaa showed that the effect of H-2-linked allele is to a large extent reduced, and that additive effects of three independently functioning dominant alleles, one located in the telomeric portion on chromosome 7, one in the centromeric portion on chromosome 14, and one linked to H-2, predispose the severe lupus nephritis, under modification by the effect of
Yaa. Thus, the epistatic effect of
Yaa contributes to the disease by modifying other predisposing genetic elements which are either functioning or silent in
Yaa-negative female mice. There were several potentially important candidate genes which may be relevant to the pathogenesis of lupus nephritis.
View full abstract