Pathogenic role of SAT1 variants in monogenic lupus

摘要：系统性红斑狼疮(SLE)是一种多因素致病的自身免疫性疾病。 由遗传、表观遗传和环境因素造成。系统性红斑狼疮的发病机制复杂。在大多数 例如，系统性红斑狼疮的遗传易感性归因于每一种常见变异的总体遗传风险 基因起到了很小的作用。然而，在少数系统性红斑狼疮病例中，特别是早发性儿童系统性红斑狼疮是由 高渗透性单基因变种。单基因形式的系统性红斑狼疮通常与强烈的家族史有关， 早发性疾病与男性性别有关，临床表现严重。单基因的鉴定 狼疮的病因虽然罕见，但对理解SLE的发病机制提供了重要的见解。在我们的预赛中 研究中，我们进行了全外显子组测序，以从两个多基因片段中确定潜在的单基因原因 每个家庭有两个患有儿童期系统性红斑狼疮的男孩。在每个家族中，我们都发现了一个外显子变体 在一个X连锁基因SAT1中。这两个变异可能导致了SAT1功能的丧失。两个变种 是以X连锁隐性方式遗传的，在群体中极其罕见(在&gt；200,000中缺失 个人)。综上所述，我们确定SAT1是一个与单基因狼疮相关的新基因。SAT1 编码亚精胺/精胺-N1-乙酰转移酶(SSAT)，这是一种限速酶，调节 多胺的分解代谢。我们假设功能丧失的SAT1变异可能导致多胺失调 导致系统性红斑狼疮风险的动态平衡。为了进一步评估SLE中STA1变异的因果关系，我们建议 通过DNA测序确定更多的SAT1变异并研究这些变异对功能的影响 使用基于细胞的检测和Pristane诱导的狼疮小鼠模型。我们建议评估SAT1的影响 MRNA剪接、蛋白质生产、SSAT酶活性、多胺水平、活性氧物种的变异 (ROS)水平和狼疮相关表型的表现。这些研究的结果将增强我们的 了解这一新基因和途径在狼疮发病机制中的作用。获得的信息可能有助于开发 靶向导致SAT1介导的风险的关键细胞和/或分子通路的药物 考虑系统性红斑狼疮的治疗。

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.