Lymphopenia in the BB Rat Model of Type 1 Diabetes is Due to a Mutation in a Novel Immune-Associated Nucleotide (Ian)-Related Gene
- Armand J. MacMurray1,4,
- Daniel H. Moralejo1,4,
- Anne E. Kwitek2,
- Elizabeth A. Rutledge1,
- Brian Van Yserloo1,
- Paul Gohlke1,
- Sara J. Speros1,
- Ben Snyder1,
- Jonathan Schaefer1,
- Sabine Bieg1,
- Jianjie Jiang1,
- Ruth A. Ettinger1,
- Jessica Fuller1,
- Terri L. Daniels1,
- Anna Pettersson1,
- Kimberly Orlebeke2,
- Bruce Birren3,
- Howard J. Jacob2,
- Eric S. Lander3, and
- Åke Lernmark1,5
Abstract
The BB (BioBreeding) rat is one of the best models of spontaneous autoimmune diabetes and is used to study non-MHC loci contributing to Type 1 diabetes. Type 1 diabetes in the diabetes-prone BB (BBDP) rat is polygenic, dependent upon mutations at several loci.Iddm1, on chromosome 4, is responsible for a lymphopenia (lyp) phenotype and is essential to diabetes. In this study, we report the positional cloning of theIddm1/lyp locus. We show that lymphopenia is due to a frameshift deletion in a novel member (Ian5) of the Immune-Associated Nucleotide (IAN)-related gene family, resulting in truncation of a significant portion of the protein. This mutation was absent in 37 other inbred rat strains that are nonlymphopenic and nondiabetic. The IAN gene family, lying within a tight cluster on rat chromosome 4, mouse chromosome 6, and human chromosome 7, is poorly characterized. Some members of the family have been shown to be expressed in mature T cells and switched on during thymic T-cell development, suggesting thatIan5 may be a key factor in T-cell development. The lymphopenia mutation may thus be useful not only to elucidate Type 1 diabetes, but also in the function of the Ian gene family as a whole.
[Sequence data reported in this paper has been deposited in GenBank and assigned the following accession nos:AF517674, AF517675, AF517676, and AF517677. Supplemental material is available online at http://depts.washington.edu/rhwlab/ and http:www.genome.org. ] The following individuals and institutions kindly provided reagents, samples, or unpublished information as indicated in the paper: K. Matsumoto and the Sir Frederick Banting Research Centre.
