Investigations into a candidate lupus risk gene expressed in plasmacytoid dendritic cells.

OBJECTIVE

We have investigated the molecular function of , a candidate risk gene for SLE exclusively expressed in plasmacytoid dendritic cells (pDCs) among peripheral leucocytes.

METHODS

We tested the independence of the association in with SLE by performing conditional analyses. We profiled the expression pattern of among circulating leucocytes at the transcript and protein levels. Using lentiviral vectors, we localised the subcellular distribution of SCAMP5 alongside the interferon secretory pathway. We analysed pDCs for the expression of and interferon production capacity by genotype. Finally, we examined pDC-specific isoforms by total RNAseq analysis and examined for genotype-associated quantitative differences therein.

RESULTS

A conditional analysis revealed evidence of an independent genetic association of with SLE. Among circulating leucocytes, is uniquely expressed in pDCs at the transcript and protein levels, with main presence in the Golgi apparatus and minor presence at the cell periphery. In live cells, SCAMP5 displayed dynamic Golgi-cell surface trafficking and localised with the interferon secretory pathway. did not differ in expression levels in pDCs between genotyped donors; however, a transient interferon secretory defect was noted in pDCs from donors carrying the risk genotype.

CONCLUSIONS

constitutes a novel SLE risk gene on the basis of genomic data and expression in a cell type widely implicated in SLE pathogenesis. While we could not find evidence of quantitative expression differences in between genotyped donors, remains an attractive gene to explore given its highly restricted expression pattern and colocalisation with interferon secretion.