Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome

Sou Niitsuma, Hiroki Kudo, Atsuo Kikuchi, Takaya Hayashi, Satoshi Kumakura, Shuhei Kobayashi, Yuko Okuyama, Naonori Kumagai, Tetsuya Niihori, Yoko Aoki, Takanori So, Ryo Funayama, Keiko Nakayama, Matsuyuki Shirota, Shuji Kondo, Shoji Kagami, Hiroyasu Tsukaguchi, Kazumoto Iijima, Shigeo Kure, Naoto Ishii

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroidresistant 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.

Original languageEnglish
Pages (from-to)283-292
Number of pages10
JournalInternational Immunology
Issue number4
Publication statusPublished - 2020 Apr 1


  • Familial nephrotic syndrome
  • Interleukin-1 receptor accessory protein
  • Myeloid-derived suppressor cell


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