A Skint6 allele potentially contributes to mouse lupus

Abstract

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.

A Variant of the Histone-Binding Protein sNASP Contributes to Mouse Lupus

“…These results suggest that the rec1c sublocus seemingly is not involved in systemic autoimmunity, but is rather aggravating its consequences. This is a contrast to the adjacent rec1d1 sublocus since the rec1d1.lpr mice showed 3-fold expanded spleen or even 10-fold enlarged lymph node relative to B6.lpr mice, and this expansion was largely accounted for T cells, suggesting that red1d1 contributes to lupus by targeting T cells (15). We have proposed a model for the genes involved in lupus pathogenesis with a first group of genes breaking tolerance, such as Ly108 in Sle1b (23), a second group amplifying/ polarizing autoimmune activation, such as Pbx1 in Sle1a (24), and a third group of genes modulating disease severity in target organs, such as the kallycrein gene family in Sle3 (25) in the NZM2410 lupus model (26).…”

“…Renal lesions were scored in a blinded manner following the previous report (7), and briefly speaking: grade 0, normal glomeruli, and evident capillary loops and unexpanded mesangium; grade 1, evident capillary loops, and widened mesangium with mild hypercellularity; grade 2, evident capillary loops, and expanded mesangium with more than moderate hypercellularity; grade 3, diminished capillary loops, swollen glomeruli, and more than 50% of all glomeruli with diffuse endocapillary proliferation; grade 4, no capillary loops, and basement membrane thickening and significant mesangial proliferation, more than 90% of all glomeruli with diffuse endocapillary proliferation. Lung pathology alterations were evaluated semi-quantitatively following the protocols in our publication (15), to briefly summarize: grade 0, normal lung architecture; grade 1, 1–10% of alveolar in lung has the pathological alterations of exudates, atelectasis and increased inflammatory cell number; grade 2, 10–25% of alveolar in lung shows the above pathological alterations and mild infiltrate of inflammatory cells around arteries and veins; grade 3, 25–50% alveolar in lung displays the above pathological alterations and moderate infiltrate of inflammatory cells around arteries and veins; grade 4, >50% alveolar in lung demonstrates the above pathological alterations and heavy infiltrate of inflammatory cells around arteries and veins.…”

“…Recently, we produced a novel recombinant rec1d1 from the rec1d sublocus (Figure 1) that narrowed down the location of the gene responsible for the severe autoimmune disease with striking lymphadenopathy in the rec1d1.lpr mice (15). The only gene in the rec1d1 interval that presented a non-synonymous mutation was Skint6 , and this mutation resulted in a truncated secretory peptide (15).…”

“…Recently, we produced a novel recombinant rec1d1 from the rec1d sublocus (Figure 1) that narrowed down the location of the gene responsible for the severe autoimmune disease with striking lymphadenopathy in the rec1d1.lpr mice (15). The only gene in the rec1d1 interval that presented a non-synonymous mutation was Skint6 , and this mutation resulted in a truncated secretory peptide (15). The Skint6 protein is mainly expressed in mouse skin, and we obtained evidence that non-hematopoietic cells expressing the rec1d1 Skint6 allele promoted T cell proliferation in vivo , suggesting that the Skint6 variant is the most likely causal gene in the rec1d1 sublocus.…”

“…The focus of this study was to analyze the phenotypes associated with the expression of rec1c , which is telomeric of rec1d1 (14, 15). When combined with lpr, rec1c showed a modest effect on autoimmune phenotypes, and greatly aggravated kidney and lung pathology.…”