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Vol. 12, Issue 7, 1029-1039, July 2002

LETTER
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. MacMurray,1,4 Daniel H. Moralejo,1,4 Anne E. Kwitek,2 Elizabeth A. Rutledge,1 Brian Van Yserloo,1 Paul Gohlke,1 Sara J. Speros,1 Ben Snyder,1 Jonathan Schaefer,1 Sabine Bieg,1 Jianjie Jiang,1 Ruth A. Ettinger,1 Jessica Fuller,1 Terri L. Daniels,1 Anna Pettersson,1 Kimberly Orlebeke,2 Bruce Birren,3 Howard J. Jacob,2 Eric S. Lander,3 and Åke Lernmark1,5

1 Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington 98195, USA; 2 Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA; 3 Whitehead/MIT Center for Genome Research, Cambridge, Massachusetts 02139, USA

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 the Iddm1/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 that Ian5 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 ] The following individuals and institutions kindly provided reagents, samples, or unpublished information as indicated in the paper: K. Matsumoto and the Sir Frederick Banting Research Centre.

4 These authors contributed equally to this work.

5 Corresponding author.

12:1029-1039 ©2002 by Cold Spring Harbor Laboratory Press  ISSN 1088-9051/02 $5.00
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