National Human Genome Research Institute, NIH, Bethesda, Maryland.
National Human Genome Research Institute, NIH, Bethesda, Maryland, and Zhejiang University, Hangzhou, China.
Arthritis Rheumatol. 2017 Sep;69(9):1832-1839. doi: 10.1002/art.40158. Epub 2017 Jul 10.
To identify a genetic cause of early-onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of the disease.
We performed whole-exome sequencing and single-nucleotide polymorphism array genotyping in family members with and without SLE. Protein and gene expression, cytokine profile, neutrophil extracellular trap (NET) formation, and presence of low-density granulocytes were evaluated in patient primary cells and serum samples.
We identified a novel, homozygous, loss-of-function mutation (p.Pro445Leufs*11) in the C1R gene. Using the Sanger method of DNA sequencing in 14 family members, we confirmed the presence of the mutation in 4 patients with SLE and in an asymptomatic 9-year-old girl. Complement levels were low in sera from patients with truncated C1r protein. Two siblings with SLE who were available for detailed evaluation exhibited strong type I interferon (IFN) inflammatory signatures despite their disease being clinically inactive at the time of sampling. The type I IFN transcriptional signature in the patients' blood correlated with disease expressivity, whereas the neutrophil signature in peripheral blood mononuclear cells was likely associated with disease severity. The female patient with SLE with the most severe phenotype presented with a stronger neutrophil signature, defined by enhanced NET formation and the presence of low-density granulocytes. Analysis of exome data for modifying alleles suggested enrichment of common SLE-associated variants in the more severely affected patients. Lupus-associated HLA alleles or HLA haplotypes were not shared among the 4 affected subjects.
Our findings revealed a novel high-penetrance mutation in C1R as the cause of monogenic SLE. Disease expressivity in this family appears to be influenced by additional common and rare genetic variants.
在一个来自土耳其的大型近亲家族中确定早发性系统性红斑狼疮（SLE）的遗传原因，并研究疾病的机制。
我们对有和没有 SLE 的家族成员进行了全外显子测序和单核苷酸多态性微阵列基因分型。在患者的原代细胞和血清样本中评估了蛋白质和基因表达、细胞因子谱、中性粒细胞胞外陷阱（NET）形成和低密粒细胞的存在。
我们在一个 C1R 基因中发现了一个新的纯合、功能丧失突变（p.Pro445Leufs*11）。通过对 14 个家族成员的 DNA 测序 Sanger 方法，我们在 4 名 SLE 患者和一名无症状的 9 岁女孩中证实了该突变的存在。截短 C1r 蛋白患者血清中的补体水平较低。2 名可供详细评估的 SLE 患者尽管在采样时疾病处于临床静止期，但表现出强烈的 I 型干扰素（IFN）炎症特征。患者血液中的 I 型 IFN 转录特征与疾病表达性相关，而外周血单核细胞中的中性粒细胞特征可能与疾病严重程度相关。患有 SLE 且表型最严重的女性患者表现出更强的中性粒细胞特征，定义为增强的 NET 形成和低密粒细胞的存在。修饰等位基因的外显子数据分析表明，在病情较重的患者中存在常见的 SLE 相关变异的富集。4 名受影响的患者之间未共享狼疮相关 HLA 等位基因或 HLA 单倍型。
我们的发现揭示了 C1R 中的一个新的高外显率突变是单基因 SLE 的原因。该家族的疾病表达性似乎受到额外的常见和罕见遗传变异的影响。
