International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F33 Alymphoplasia is Caused by a Point Mutation in NF-Kappa B Inducing Kinase (NIK) Gene

Kazuhiro Kitada1, Reiko Shinkura2, Fumihiko Matsuda2, Kei Tashiro3, Kouichi Ikita2, Katsumi Kogishi1, Misao Suzuki4, Sigeki Miyawaki5, Tasuku Hpnjo2, Tadao Serikawa1. 1 Institute of Laboratory Animals; 2Department of Medical Chemistry, Graduate School of Medicine, Kyoto University; 3Center for Molecular Biology and Genetics, Kyoto University; 4Center for Animal Resources and Development, Kumamoto University; 5Nippon Shinyaku Co. Ltd.

The aly (Alymphoplasia) mutation in mice causes various immunological abnormalities including systemic absence of lymph nodes (LN) and Peyer's patches (PP), isorganized splenic and thymic structures, accompanied with immunodeficiency. Here, in order to identify the responsible gene, we executed the positional cloning study. With the use of 2,803 backcross progenies between ALY and MSM, an inbred strain derived from Japanese wild mice (Mus musculus molossinus), we localized the mutation within 264kb genomic region on the chromosome 11. The entire sequence was determined by shot gun method and exons were predicted by a computer program GRAIL, along with exon trapping and cDNA screening. As a result, we identified 6 transcription units within the region. Out of them, a point mutation (G to A) was found in NF-kappa B inducing kinase (NIK) gene which involves an amino acid substitution (G855R) in the C-terminal region of NIK. The residue is conservative among laboratory mice, Mus musculus molossinus, Mus spretus and even humans. Transgenic complementation with wild type of Nik under H-2Kd promoter restored the normal structures in LN, PP, spleen and thymus, and the normal immune response in aly/aly mice. Moreover, in vivo experiments demonstrated that this mutation abolished a dominant-negative effect in a kinase-truncated NIK as for NF-kappa B activation by an excess of lymphotoxin beta receptor (LTbR). These results clearly show that NIK has a critical role in the development of lymphoid tissues.


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