Pathogenic role of SAT1 variants in monogenic lupus

SAT1 变异在单基因狼疮中的致病作用

• 批准号: 9920091
• 负责人: BETTY P TSAO
• 金额: $ 16.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920091
• 关键词: Accounting; Affect; Autoimmune Diseases; Biological Assay; Candidate Disease Gene; Case-Control Studies; Cells; Childhood; Classical Complement Pathway; Clinical; Complex; DNA sequencing; Data; Disease; Environmental Risk Factor; Enzymes; Epigenetic Process; Etiology; Exhibits; Family; Family member; Gender; Gene Expression; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Homeostasis; Individual; Inheritance Patterns; Inherited; Knock-out; Knockout Mice; Lead; Link; Lupus; Measures; Mediating; Messenger RNA; Modeling; Molecular; Mothers; Mus; Nonsense Codon; Odds Ratio; Onset of illness; Parents; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Polyamine Catabolism; Polyamines; Population; Pristane; Production; Proteins; RNA Interference; RNA Splicing; Reactive Oxygen Species; Recording of previous events; Risk; Role; Spermidine/Spermine N1-Acetyltransferase; Systemic Lupus Erythematosus; Transcript; Variant; X Chromosome; base; boys; case control; cytokine; early onset; enzyme activity; exome; exome sequencing; genetic variant; genome database; genome wide association study; insight; knock-down; loss of function; lupus prone mice; lupus-like; male; mouse model; new therapeutic target; novel; pediatric lupus; rare variant; risk variant

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.

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共同作用。SLE的发病机制复杂。在大多数 例，SLE的遗传易感性归因于多种常见变异的总体遗传风险， 基因的影响很小。然而，在少数SLE病例中，特别是早发性儿童SLE， 高度外显的单基因变异。单基因型SLE通常与强家族史有关， 早发性疾病和男性性别，并导致严重的临床表现。单基因鉴定 狼疮的病因，虽然罕见，提供了重要的洞察了解SLE发病机制。在我们的初步调查中 研究中，我们进行了全外显子组测序，以确定潜在的单基因原因，从两个多重 每个家庭有两个男孩患有儿童期SLE。在每个家族中，我们发现了一个外显子变异 X染色体连锁基因SAT 1这两种变体可能导致SAT 1功能丧失。两种变体 以X连锁隐性模式遗传，在人群中极为罕见（> 200，000人中不存在） 个人）。总之，我们确定SAT 1作为一个新的基因与单基因狼疮。Sat1 编码亚精胺/精胺-N1-乙酰转移酶（SSAT），这是一种限速酶， 聚胺催化剂。我们假设功能丧失的SAT 1变异体可能导致多胺失调 体内平衡，这赋予SLE的风险。为了进一步评估STA 1变异体在SLE中的因果关系，我们建议 通过DNA测序鉴定其他SAT 1变体，并研究这些变体的功能影响 使用基于细胞的分析和降植烷诱导的狼疮小鼠模型。我们建议评估SAT 1的影响 mRNA剪接变异体、蛋白质产生、SSAT酶活性、多胺水平、活性氧 (ROS)狼疮相关表型的水平和表现。这些研究的结果将提高我们的 了解这种新的基因和途径在狼疮发病机制。获得的信息可以帮助开发 靶向负责SAT 1介导的风险的关键细胞和/或分子途径的药物 考虑SLE治疗。