Homozygous Fas lpr (former nomenclature was Tnfrsf6 lpr) mice develop severe lymphoma and show an absence of spontaneous diabetes and insulitis.
Christophe Benoist, Joslin Diabetes Center
NOD mice homozygous for the Tnfrsf6 lpr mutation are deficient in Fas antigen expressed on cell surfaces, and the disruption of the Fas-mediated apoptotic pathway results in severe lymphoma in NOD by 4 months of age. This lymphoma is characterized by an expansion of unusual CD4 -, CD8 -, CD3 low , B220 + lymphocytes.
Forty week-old NOD mice homozygous for the Tnfrsf6 lpr mutation are completely protected from spontaneous diabetes and insulitis (as compared to 68% diabetes incidence in the control NOD), even after adoptive transfer of lymphocytes from diabetic NOD mice (0% diabetes incidence 12 weeks post transfer, as compared to NOD controls with 85% incidence 12 weeks post transfer). Recent evidence indicates that Fas-deficient NOD mice are resistant to the adoptive transfer because the abnormal subset of CD4 -, CD8 -, CD3 low , B220 + lymphocytes, which express FasL, destroy the donor T cells via the Fas-FasL apoptotic pathway. When homozygous mutant mice are treated with FasL antibody within the adoptive transfer protocol, diabetes protection is incomplete (60% of female homozygotes developed diabetes vs. 80% in control NODs). (Itoh et. al 1997; Su et. al 2000; Kim et. al 2000)
The Tnfrsf6lpr spontaneous mutation originally arose at the 12th generation of inbreeding of strain MRL/Mp, derived from strains LG, AKR, C3H, and C57BL/6. At the subsequent generation, MRL/Mp lymphoproliferative positive and negative sublines, which had an estimated 89% of their genomes in common, were separated. The mutant gene was then transferred to the MRL negative strain by 5 cycles of cross-intercross matings thus reducing the estimate of residual heterozygosity to 1% from 11% (Stock No. 000485). Additionally, the mutation was transferred to both C57BL/6J (Stock No. 000482) and C3H/HeJ (Stock No. 000480). The Tnfrsf6lpr mutation was then transferred to the NOD inbred strain for 16 generations, after which it was imported into The Jackson Laboratory and brother-sister mating began.
|Allele Type||Spontaneous (Hypomorph)|
|Allele Synonym(s)||Fas-; Fas-def; lpr; MRL/lpr; Tnfrf6lpr; Tnfrsf6lpr; Tnfrsf6lpr|
|Gene Symbol and Name||Fas, Fas (TNF receptor superfamily member 6)|
|Strain of Origin||MRL/Mp|
|General Note||Faslpr, lymphoproliferation, recessive. This mutation was found during inbreeding of a strain MRL/Mp derived from crosses among strains LG, AKR, C3H, and C57BL/6. The resemblance has led to extensive use of Faslpr mice in attempts to determine the etiology of SLE and to evaluate therapies. However, the human APT1 gene (OMIM 134637) encodes the FAS antigen; Tnfrsf6 is not the homolog of the human (SLE) gene.The Cd72c haplotype is a modifier of Faslpr-induced autoimmune disease. J:204782|
|Molecular Note||Southern blotting experiments indicated that the mutation is a genomic rearrangement within the gene, probably within the second intron. Sequencing of genomic DNA and RT-PCR products from homozygous mutant mice revealed the insertion of an early transposable element (ETn) into intron 2. RT-PCR analysis of liver and thymus mRNA showed that the presence of the ETn leads to premature termination of transcription at the long terminal repeat (LTR) of the ETn and aberrant mRNA splicing. The mutation is "leaky," however, as full-length mRNA and a longer splice product incorporating a segment of the ETn as an extra intron are detected in the thymus at low levels.|
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