Journal
IMMUNITY
Volume 15, Issue 5, Pages 775-785Publisher
CELL PRESS
DOI: 10.1016/S1074-7613(01)00228-X
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Funding
- NCI NIH HHS [R0-1 CA53615, CA46934] Funding Source: Medline
- NIAID NIH HHS [K0-8 AI01516, R0-1 AI49901, R0-1 AI31105] Funding Source: Medline
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The major murine systemic lupus erythematosus (SLE) susceptibility locus, Sle1, corresponds to three loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Sle1c contains Cr2, which encodes complement receptors 1 and 2 (CR1/CR2, CD35/CD21). NZM2410/NZW Cr2 exhibits a single nucleotide polymorphism that introduces a novel glycosylation site, resulting in higher molecular weight proteins. This polymorphism, located in the Cad binding domain, reduces ligand binding and receptor-mediated cell signaling. Molecular modeling based on the recently solved CR2 structure in complex with Cad reveals that this glycosylation interferes with receptor dimerization. These data demonstrate a functionally significant phenotype for the NZM2410 Cr2 allele and strongly support its role as a lupus susceptibility gene.
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