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Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci.

Publication ,  Journal Article
Watson, ML; Rao, JK; Gilkeson, GS; Ruiz, P; Eicher, EM; Pisetsky, DS; Matsuzawa, A; Rochelle, JM; Seldin, MF
Published in: J Exp Med
December 1, 1992

In MRL mice, the mostly recessive lpr mutation results in both the accumulation of CD4-, CD8-, CD3+ T cells in lymphoid tissue and many features of generalized autoimmune disease, including immune complex glomerulonephritis. To positionally clone the lpr mutation and analyze the effects of background genes, backcross offspring were examined from the cross: (MRL/MpJ-lpr x CAST/Ei)F1 x MRL/MpJ-lpr. The lpr gene was found to be closely linked to a mouse chromosome 19 marker defined by a variation of a Fas gene restriction fragment. Our results identified differences in RNA expression and differences in the genomic organization of the Fas gene between normal and lpr mice, and confirm the recent report that a mutation in the Fas apoptosis gene is the lpr mutation. However, our results also indicate that the Fas gene is expressed in spleen cells from normal mice, and spleen and lymph node cells from mice with a second mutation at the lpr locus (lprcg). Together these results suggest that altered Fas transcription results in the failure of lymphocytes to undergo programmed cell death and may lead to an altered immune cell repertoire. This mechanism may explain certain central and peripheral defects in tolerance that are present in autoimmune disease. The current study also demonstrates the profound effect of background genes on the degree of nephritis, lymphadenopathy, and anti-DNA antibody production. Of major note, our studies suggest the identification of chromosomal positions for genes that modify nephritis. Analysis of the backcross mice for markers covering most of the mouse genome suggests that over 50% of the variance in renal disease is attributable to quantitative trait loci on mouse chromosomes 7 and 12. Moreover, this study provides a model for dissecting the complex genetic interactions that result in manifestations of autoimmune disease.

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Published In

J Exp Med

DOI

ISSN

0022-1007

Publication Date

December 1, 1992

Volume

176

Issue

6

Start / End Page

1645 / 1656

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Spleen
  • Software
  • Restriction Mapping
  • Polymerase Chain Reaction
  • Mice, Mutant Strains
  • Mice, Inbred CBA
  • Mice
  • Male
  • Lymph Nodes
 

Citation

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MLA
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Watson, M. L., Rao, J. K., Gilkeson, G. S., Ruiz, P., Eicher, E. M., Pisetsky, D. S., … Seldin, M. F. (1992). Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med, 176(6), 1645–1656. https://doi.org/10.1084/jem.176.6.1645
Watson, M. L., J. K. Rao, G. S. Gilkeson, P. Ruiz, E. M. Eicher, D. S. Pisetsky, A. Matsuzawa, J. M. Rochelle, and M. F. Seldin. “Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci.J Exp Med 176, no. 6 (December 1, 1992): 1645–56. https://doi.org/10.1084/jem.176.6.1645.
Watson ML, Rao JK, Gilkeson GS, Ruiz P, Eicher EM, Pisetsky DS, et al. Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med. 1992 Dec 1;176(6):1645–56.
Watson, M. L., et al. “Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci.J Exp Med, vol. 176, no. 6, Dec. 1992, pp. 1645–56. Pubmed, doi:10.1084/jem.176.6.1645.
Watson ML, Rao JK, Gilkeson GS, Ruiz P, Eicher EM, Pisetsky DS, Matsuzawa A, Rochelle JM, Seldin MF. Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med. 1992 Dec 1;176(6):1645–1656.

Published In

J Exp Med

DOI

ISSN

0022-1007

Publication Date

December 1, 1992

Volume

176

Issue

6

Start / End Page

1645 / 1656

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Spleen
  • Software
  • Restriction Mapping
  • Polymerase Chain Reaction
  • Mice, Mutant Strains
  • Mice, Inbred CBA
  • Mice
  • Male
  • Lymph Nodes