Our previous study uncovered that the overlapping region of murine lupus susceptibility Sle2c1rec1a and Sle2c1rec1d subloci is strongly associated with lymphadenopathy and systemic autoimmunity. In order to identify the specific candidate gene, we generated a novel shorter recombinant, named as Sle2c1re1d1 (rec1d1), from Sle2c1rec1d sublocus (rec1d). The rec1d1 interval corresponds precisely to the overlapping region of Sle2c1rec1a and Sle2c1rec1d subloci. Functionally, this rec1d1 sublocus showed a strong epistatic interaction with lpr, similar to that seen with Sle2c1rec1a or.Sle2c1rec1d. The Skint6 gene in the red1d1 interval was identified to have a point mutation, which inserts a premature stop codon and converts the membrane Skint6 protein into a truncated secretory peptide. However, other protein-coding genes in the rec1d1 interval have no mutation in exon sequence. The heterozygous rec1d1 interval in B6.lpr demonstrates exacerbated autoimmunity. For example, non-hematopoietic stem cell-derived cells of the B6.Sle2c1rec1d1.lpr mice promote T-cell proliferation in vivo. These findings led us to conclude that the Skint6 variant in the rec1d1 interval is the most likely causative gene of mouse lupus.
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