Objectives Families that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus. Methods Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional patients with SLE. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively. Results The two familial ultra-rare, predicted loss-of-function (LOF) SAT1 variants exhibited X-linked recessive Mendelian inheritance in two unrelated African–American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous female Sat1 p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leucocyte infiltration, proteinuria and elevated expression of type I interferon-inducible genes. SAT1 is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3 +CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3 +CD4+ T cells correlated with decreased plasma levels of spermine in treatment-naive, incipient SLE patients. Conclusions We identified two novel SAT1 LOF variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism and identified SAT1 LOF variants as new monogenic causes for SLE. Data are available upon reasonable request.

中文翻译：

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SAT1 的功能缺失变异导致 X 连锁儿童期发病的系统性红斑狼疮


目标 包含多个患有儿童期发病的系统性红斑狼疮 (SLE) 兄弟姐妹的家庭可能具有很强的遗传倾向。我们进行了全外显子组测序 (WES)，以识别家族性罕见风险变异并评估其对狼疮的影响。方法 Sanger 测序验证了 WES 发现的两种极其罕见的预测致病风险变异，并在另外 562 名 SLE 患者中鉴定了其他变异。分别使用 Minigene 测定和 CRISPR/Cas9 介导的敲入 (KI) 小鼠评估剪接位点变体和移码变体的影响。结果 两个家族性极其罕见、预测功能丧失 (LOF) SAT1 变体在两个不相关的非裔美国家庭中表现出 X 连锁隐性孟德尔遗传。每个 LOF 变异均从未受影响的杂合母亲遗传给她患有儿童期 SLE 的两个儿子。 p.Asp40Tyr 变体影响剪接供体位点，导致有害的转录本。年轻的半合子雄性和纯合性雌性 Sat1 p.Glu92Leufs*6 KI 小鼠自发出现脾肿大、肾小球增大、白细胞浸润、蛋白尿和 I 型干扰素诱导基因表达升高。 SAT1 在中性粒细胞中高度表达，并编码亚精胺/精胺-N1-乙酰转移酶 1 (SSAT1)，这是多胺分解代谢中的限速酶。年轻雄性 KI 小鼠表现出中性粒细胞缺陷和 Foxp3 + CD4 + T 细胞亚群比例下降。在初治 SLE 患者中，循环中性粒细胞计数和 Foxp3 + CD4 + T 细胞的比例与血浆精胺水平降低相关。 结论 我们鉴定了两种新的 SAT1 LOF 变异，显示了移码变异赋予小鼠狼疮的能力，强调了多胺分解代谢失调的致病作用，并将 SAT1 LOF 变异确定为 SLE 的新单基因原因。数据可根据合理要求提供。