Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase

Nat Genet. 1999 May;22(1):74-7. doi: 10.1038/8780.


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 beta-receptor (Ltbeta r, encoded by Ltbr) provides a critical signal for LN genesis in mice, the aly locus on chromosome 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-kappa b-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-kappa b activation induced by an excess of Ltbeta r. Our observations agree with previous reports that Ltbeta r-deficient mice showed defects in LN genesis and that Nik is a common mediator of Nf-kappa b 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), suggesting it acts downstream of TRAF-associating receptor signalling pathways, including Tnfr, Cd40, Cd30 and Ltbeta r. 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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • DNA, Complementary / chemistry
  • DNA, Complementary / genetics
  • Humans
  • Lymph Nodes / enzymology
  • Lymph Nodes / pathology*
  • Lymphotoxin beta Receptor
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peyer's Patches / enzymology
  • Peyer's Patches / pathology*
  • Phenotype
  • Point Mutation
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Spleen / enzymology
  • Spleen / pathology
  • Thymus Gland / enzymology
  • Thymus Gland / pathology


  • DNA, Complementary
  • LTBR protein, human
  • Ltbr protein, mouse
  • Lymphotoxin beta Receptor
  • Receptors, Tumor Necrosis Factor
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase

Associated data

  • GENBANK/AF143094