Pathogenic role of SAT1 variants in monogenic lupus

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Abstract: Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease with a multifactorial etiology contributed by genetic, epigenetic and environmental factors. The pathogenesis of SLE is complex. In most cases, genetic susceptibility of SLE is attributed to the overall genetic risk of multiple common variants that each gene confers a small effect. However, in few cases of SLE, especially early-onset pediatric SLE, is caused by highly penetrant single gene variants. Monogenic forms of SLE are usually associated with strong family history, early-onset disease and male gender and result in severe clinical manifestations. Identification of monogenic causes of lupus, although rare, offers important insight into understanding SLE pathogenesis. In our preliminary study, we carried out whole-exome sequencing to identify underlying monogenic causes from two multiplex families that each family has two boys with childhood onset SLE. In each family, we identified an exonic variant in an X-linked gene SAT1. These two variants presumably lead to the loss-of-function of SAT1. Both variants are inherited in the X-linked recessive pattern and they are extremely rare in the population (absent in > 200,000 individuals). Taken together, we identified SAT1 as a novel gene associated with monogenic lupus. SAT1 encodes the spermidine/spermine-N1-acetyltransferase (SSAT), a rate-limiting enzyme that regulates the catabolism of polyamine. We hypothesize that loss-of-function SAT1 variants may cause dysregulated polyamine homeostasis which confers risk of SLE. To further evaluate the causality of STA1 variants in SLE, we propose to identify additional SAT1 variants by DNA sequencing and investigate the functional impact of these variants using cell-based assays and pristane-induced mouse model of lupus. We propose to assess the impact of SAT1 variants on mRNA splicing, protein production, SSAT enzyme activity, polyamine levels, reactive oxygen species (ROS) levels and manifestation of lupus-related phenotypes. Results from these studies will enhance our understanding of this novel gene and pathway in lupus pathogenesis. The information gained could help develop drugs to target the pivotal cellular and/ or molecular pathways responsible for SAT1-mediated risk for consideration of SLE therapies.