論文 - 詳細
| RRC ID | 71981 |
|---|---|
| 著者 | Yamashita M, Kuehn HS, Okuyama K, Okada S, Inoue Y, Mitsuiki N, Imai K, Takagi M, Kanegane H, Takeuchi M, Shimojo N, Tsumura M, Padhi AK, Zhang KYJ, Boisson B, Casanova JL, Ohara O, Rosenzweig SD, Taniuchi I, Morio T. |
| タイトル | A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS. |
| ジャーナル | Nat Immunol |
| Abstract |
In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner. |
| 巻・号 | 22(7) |
| ページ | 893-903 |
| 公開日 | 2021-7-1 |
| DOI | 10.1038/s41590-021-00951-z |
| PII | 10.1038/s41590-021-00951-z |
| PMID | 34155405 |
| PMC | PMC8958960 |
| MeSH | Adaptive Immunity* Animals B-Lymphocytes / immunology B-Lymphocytes / metabolism* COS Cells Cell Differentiation* Chlorocebus aethiops Disease Models, Animal Female HEK293 Cells Humans Ikaros Transcription Factor / genetics Ikaros Transcription Factor / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Mutation, Missense NIH 3T3 Cells Primary Immunodeficiency Diseases / genetics Primary Immunodeficiency Diseases / immunology Primary Immunodeficiency Diseases / metabolism* Protein Binding Protein Interaction Domains and Motifs Protein Multimerization Signal Transduction T-Lymphocytes / immunology T-Lymphocytes / metabolism* |
| IF | 20.479 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 86 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | NALM-6(RCB1933) |