Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1β, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1β. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1β for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.

中文翻译：

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类固醇敏感性肾病综合征患者中IL1RAP的双等位基因变异/突变。

肾病综合征（NS）是一种以严重的蛋白尿和低蛋白血症为特征的肾脏疾病。尽管一些单基因突变与类固醇耐药性NS有关，但尚不清楚类固醇敏感性NS（SSNS）的致病基因。当试图通过全外显子组测序鉴定与SSNS相关的致病基因时，我们发现白介素1受体附件的复合杂合变异/突变（c.524T> C； p.I175T和c.662G> A； p.R221H） SSNS的两个兄弟姐妹中的蛋白（IL1RAP）基因。兄弟姐妹的父母健康，每个父母都携带不同的杂合IL1RAP变异/突变。由于IL1RAP是功能性白介素1受体（IL-1R）的关键亚基，因此我们研究了这些变体对IL-1R亚基功能的影响。当受IL-1β刺激时，与健康家庭成员的细胞相比，SSNS兄弟姐妹的外周血单核细胞产生的细胞因子水平显着降低。而且，在造血细胞系上重构的具有变体IL1RAP亚基的IL-1R受损的结合能力和对IL-1β的低反应性。因此，在这些NS患者中发现的IL1RAP中的氨基酸取代是功能失调的变异/突变。此外，在Il1rap-/-小鼠的肾脏中，需要分化为IL-1β的髓样抑制细胞的数量明显减少，尽管这些小鼠在用脂多糖治疗的急性肾病损伤中并未显示蛋白尿明显增加。一起，