Genetic analysis of MRL-lpr mice: Relationship of the fas apoptosis gene to disease manifestations and renal disease-modifying loci

Mark L. Watson, Jaya K. Rao, Gary S. Gilkeson, Phillip Ruiz, Eva M. Eicher, David S. Pisetsky, Akio Matsuzawa, Julie M. Rochelle, Michael F. Seldin

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Abstract

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.

Original languageEnglish
Pages (from-to)1645-1656
Number of pages12
JournalJournal of Experimental Medicine
Volume176
Issue number6
StatePublished - Dec 1 1992

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Inbred MRL lpr Mouse
Apoptosis
Kidney
Genes
Mutation
Autoimmune Diseases
Nephritis
Spleen
Chromosomes, Human, Pair 19
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 7
Gene Order
Quantitative Trait Loci
Antinuclear Antibodies
Lymphoid Tissue
Glomerulonephritis
Antigen-Antibody Complex
Genetic Markers
Antibody Formation
Cell Death

ASJC Scopus subject areas

  • Immunology

Cite this

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. Journal of Experimental Medicine, 176(6), 1645-1656.

Genetic analysis of MRL-lpr mice : Relationship of the fas apoptosis gene to disease manifestations and renal disease-modifying loci. / Watson, Mark L.; Rao, Jaya K.; Gilkeson, Gary S.; Ruiz, Phillip; Eicher, Eva M.; Pisetsky, David S.; Matsuzawa, Akio; Rochelle, Julie M.; Seldin, Michael F.

In: Journal of Experimental Medicine, Vol. 176, No. 6, 01.12.1992, p. 1645-1656.

Research output: Contribution to journalArticle

Watson, ML, Rao, JK, Gilkeson, GS, Ruiz, P, Eicher, EM, Pisetsky, DS, Matsuzawa, A, Rochelle, JM & Seldin, MF 1992, 'Genetic analysis of MRL-lpr mice: Relationship of the fas apoptosis gene to disease manifestations and renal disease-modifying loci', Journal of Experimental Medicine, vol. 176, no. 6, pp. 1645-1656.
Watson, Mark L. ; Rao, Jaya K. ; Gilkeson, Gary S. ; Ruiz, Phillip ; Eicher, Eva M. ; Pisetsky, David S. ; Matsuzawa, Akio ; Rochelle, Julie M. ; Seldin, Michael F. / Genetic analysis of MRL-lpr mice : Relationship of the fas apoptosis gene to disease manifestations and renal disease-modifying loci. In: Journal of Experimental Medicine. 1992 ; Vol. 176, No. 6. pp. 1645-1656.
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abstract = "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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AU - Ruiz, Phillip

AU - Eicher, Eva M.

AU - Pisetsky, David S.

AU - Matsuzawa, Akio

AU - Rochelle, Julie M.

AU - Seldin, Michael F.

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