International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E5 Genetic and Functional Characterization of the Cluster of SLE-Susceptibility Loci on Mouse Telomeric Chromosome 1

Laurence Morel1, Byron P. Croker1, Kim R. Blenman1, and Edward K. Wakeland2. 1Department of Pathology, University of Florida; 2Center for Immunology, University of Texas Southwestern Medical Center

Sle1 on murine chr. 1 is a key locus to SLE pathogenesis in the NZM2410 model. A group of strong susceptibility loci has been mapped in the1 q31-42 synthenic region in humans. Sle1 mediates the loss of tolerance to H2A/H2B/DNA subnucleosomes, an early step in the pathogenetic cascade. This locus is necessary for the full development of SLE, and its suppression by an MHC-linked locus results in the complete abrogation of the autoimmune process. Sle1 engages in epistatic interactions with the NZW and NZB genomes, and with the BXSB- derived Yaa locus, resulting in synergetic phenotypes that are different from those mediated the single loci, or the NZW or NZB genomes alone.

In the process of fine-mapping the position of Sle1, we have discovered that it corresponds to a cluster of at least 3 loci, Sle1a, -b, and -c, with Sle1a and Sle1b linked within 2.4 cM in a location corresponding to the initial mapping of Sle1, and Sle1c located at the very telomeric end of chr. 1.

The initial serological ans cellular characterization of these 3 loci presented here suggests that they contribute differently to the autoimmune process.

In addition, we have characterized the Sle loci in combination with the NZW genome in (B6.NZMc1 sub-strains X NZW)F1 progeny. This analysis has allowed to attribute each of the 2 major Sle1 phenotypes, the dominant anti-chromatin antibody production and the recessive glomerulonephritis susceptibility, to different loci.



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