Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome
| Autor: | Shuhei Kobayashi, Shigeo Kure, Hiroki Kudo, Atsuo Kikuchi, Satoshi Kumakura, Naoto Ishii, Sou Niitsuma, Kazumoto Iijima, Shoji Kagami, Matsuyuki Shirota, Takaya Hayashi, Takanori So, Shuji Kondo, Naonori Kumagai, Hiroyasu Tsukaguchi, Keiko Nakayama, Yoko Aoki, Tetsuya Niihori, Yuko Okuyama, Ryo Funayama |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides medicine.medical_specialty Nephrotic Syndrome medicine.medical_treatment Immunology 030232 urology & nephrology Biology Compound heterozygosity medicine.disease_cause Peripheral blood mononuclear cell 03 medical and health sciences Mice 0302 clinical medicine Internal medicine medicine Immunology and Allergy Animals Humans Receptor Gene Kidney Mutation Siblings Infant Newborn Genetic Variation General Medicine medicine.disease Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Endocrinology Cytokine Child Preschool Female Steroids Interleukin-1 Receptor Accessory Protein Nephrotic syndrome |
| Zdroj: | International immunology. 32(4) |
| ISSN: | 1460-2377 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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