1. Lymphopenia in the BB Rat Model of Type 1 Diabetes is Due to a Mutation in a Novel Immune-Associated Nucleotide (Ian)-Related Gene
- Author
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Anna Pettersson, Anne E. Kwitek, Bruce W. Birren, Howard J. Jacob, Armand J. MacMurray, Eric S. Lander, Ruth A. Ettinger, Sabine Bieg, Terri Daniels, Brian Van Yserloo, Elizabeth A. Rutledge, Sara J. Speros, Jessica M. Fuller, Åke Lernmark, Paul Gohlke, Ben Snyder, Kimberly Orlebeke, Daniel H. Moralejo, Jonathan B. Schaefer, and Jianjie Jiang
- Subjects
Letter ,Positional cloning ,Rats, Inbred OLETF ,Molecular Sequence Data ,Locus (genetics) ,Biology ,Frameshift mutation ,Mice ,Animals, Congenic ,GTP-Binding Proteins ,Lymphopenia ,Genetics ,Animals ,Humans ,Gene family ,Rats, Inbred BB ,Amino Acid Sequence ,Genetics (clinical) ,Sequence Deletion ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,Rats, Inbred LEC ,Chromosome 7 (human) ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,Hematopoietic Stem Cells ,Phenotype ,Molecular biology ,Rats, Inbred F344 ,Rats ,Disease Models, Animal ,Diabetes Mellitus, Type 1 ,Chromosome 4 ,Protein Tyrosine Phosphatases ,Apoptosis Regulatory Proteins ,Biobreeding rat - 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/lyplocus. 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 thatIan5may 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 theIangene family as a whole.[Sequence data reported in this paper has been deposited in GenBank and assigned the following accession nos:AF517674,AF517675,AF517676, andAF517677. Supplemental material is available online athttp://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.
- Published
- 2002