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

• Published in: International immunology 2020-04, Vol.32 (4), p.283-292
• Main Authors: Niitsuma, Sou, Kudo, Hiroki, Kikuchi, Atsuo, Hayashi, Takaya, Kumakura, Satoshi, Kobayashi, Shuhei, Okuyama, Yuko, Kumagai, Naonori, Niihori, Tetsuya, Aoki, Yoko, So, Takanori, Funayama, Ryo, Nakayama, Keiko, Shirota, Matsuyuki, Kondo, Shuji, Kagami, Shoji, Tsukaguchi, Hiroyasu, Iijima, Kazumoto, Kure, Shigeo, Ishii, Naoto
• Format: Article
• Language: English
• ISSN: 1460-2377; 1460-2377
• DOI: 10.1093/intimm/dxz081

Abstract 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. IL1RAP has a role in nephrotic syndrome