Alymphoplasia is caused by a point mutation in the mouse gene encoding nf-κb-inducing kinase

Reiko Shinkura, Kazuhiro Kitada, Fumihiko Matsuda, Kei Tashiro, Koichi Ikuta, Misao Suzuki, Katsumi Kogishi, Tadao Serikawa, Tasuku Honjo

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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 immunodeficiency. 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 mice, 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 kinase (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 genesis and that Nik is a common mediator of Nf-κb activation by the tumour necrosis factor (TNF) receptor family. 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 18-21). 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.

Original languageEnglish (US)
Pages (from-to)74-77
Number of pages4
JournalNature Genetics
Volume22
Issue number1
DOIs
StatePublished - May 1 1999

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Point Mutation
Phosphotransferases
Lymphotoxin-alpha
Lymph Nodes
Genes
Peyer's Patches
Chromosomes, Human, Pair 11
Mutation
Tumor Necrosis Factor Receptors
Amino Acid Substitution
Thymus Gland
Signal Transduction
Spleen
Alleles
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

Shinkura, R., Kitada, K., Matsuda, F., Tashiro, K., Ikuta, K., Suzuki, M., ... Honjo, T. (1999). Alymphoplasia is caused by a point mutation in the mouse gene encoding nf-κb-inducing kinase. Nature Genetics, 22(1), 74-77. https://doi.org/10.1038/8780

Alymphoplasia is caused by a point mutation in the mouse gene encoding nf-κb-inducing kinase. / Shinkura, Reiko; Kitada, Kazuhiro; Matsuda, Fumihiko; Tashiro, Kei; Ikuta, Koichi; Suzuki, Misao; Kogishi, Katsumi; Serikawa, Tadao; Honjo, Tasuku.

In: Nature Genetics, Vol. 22, No. 1, 01.05.1999, p. 74-77.

Research output: Contribution to journalArticle

Shinkura, R, Kitada, K, Matsuda, F, Tashiro, K, Ikuta, K, Suzuki, M, Kogishi, K, Serikawa, T & Honjo, T 1999, 'Alymphoplasia is caused by a point mutation in the mouse gene encoding nf-κb-inducing kinase', Nature Genetics, vol. 22, no. 1, pp. 74-77. https://doi.org/10.1038/8780
Shinkura, Reiko ; Kitada, Kazuhiro ; Matsuda, Fumihiko ; Tashiro, Kei ; Ikuta, Koichi ; Suzuki, Misao ; Kogishi, Katsumi ; Serikawa, Tadao ; Honjo, Tasuku. / Alymphoplasia is caused by a point mutation in the mouse gene encoding nf-κb-inducing kinase. In: Nature Genetics. 1999 ; Vol. 22, No. 1. pp. 74-77.
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