Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κb-inducing kinase (original) (raw)

Nature Genetics volume 22, pages 74–77 (1999)Cite this article

Abstract

The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes (LN) and Peyer's patches (PP) and disorganized splenic and thymic structures with immunodeficiency1,2,3. Although recent reports have shown that the interaction between lymphotoxin (LT) and the LT β-receptor (Ltβr, encoded by Ltbr ) provides a critical signal for LN genesis in mice4,5,6,7,8,9,10, the aly locus on chromosome 11 (ref. 11) is distinct from those for LT and its receptor. We found that the aly allele carries a point mutation causing an amino acid substitution in the carboxy-terminal interaction domain of Nf-κb-inducing kinase12,13 (Nik, encoded by the gene Nik). Transgenic complementation with wild-type Nik restored the normal structures of LN, PP, spleen and thymus, and the normal immune response in aly/aly mice. In addition, the aly mutation in a kinase domain-truncated Nik abolished its dominant-negative effect on Nf-κb activation induced by an excess of Ltβr. Our observations agree with previous reports that _Ltβr_-deficient mice showed defects in LN genesis4 and that Nik is a common mediator of Nf-κb activation by the tumour necrosis factor (TNF) receptor family12,13. Nik is able to interact with members of the TRAF family (Traf1, 2, 3, 5 and 6; ref. 13), suggesting it acts downstream of TRAF-associating receptor signalling pathways, including Tnfr ( ref. 12), Cd40 (Refs 14, 15), Cd30 (Refs 16, 17) and Ltβr (refs 18, 19, 20, 21). The phenotypes of aly/aly mice are more severe than those of Ltbr –/– mice, however, indicating involvement of Nik in signal transduction mediated by other receptors.

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Acknowledgements

We thank A. Shimizu, S. Nishikawa and H. Yoshida for discussions and technical suggestions; S. Miyawaki for animals; M. Kosco-Vilbois for FDC-M1 antibody; S. Miyamoto for Nf-κb-dependent luciferase reporter gene plasmids; M. Yamazaki, K. Watanabe, C. Sugawara and Y. Fukuzumi for large-scale sequencing; M. Tanaka, N. Tomikawa and H. Kurooka for technical assistance; and K. Fukui for help in preparation of the manuscript.

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  1. Reiko Shinkura and Kazuhiro Kitada: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Chemistry, Kyoto University, Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan
    Reiko Shinkura, Fumihiko Matsuda, Koichi Ikuta & Tasuku Honjo
  2. Institute of Laboratory Animals, Kyoto University, Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan
    Kazuhiro Kitada, Katsumi Kogishi & Tadao Serikawa
  3. Center for Molecular Biology and Genetics, Kyoto University, Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan
    Kei Tashiro
  4. Center for Animal Resources and Development, Kumamoto University, Kuhonji, Kumamoto, 862-0976, Japan
    Misao Suzuki

Authors

  1. Reiko Shinkura
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  2. Kazuhiro Kitada
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  3. Fumihiko Matsuda
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  4. Kei Tashiro
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  5. Koichi Ikuta
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  6. Misao Suzuki
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  7. Katsumi Kogishi
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  8. Tadao Serikawa
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  9. Tasuku Honjo
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Correspondence toTasuku Honjo.

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Shinkura, R., Kitada, K., Matsuda, F. et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κb-inducing kinase.Nat Genet 22, 74–77 (1999). https://doi.org/10.1038/8780

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