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Cblb is a major susceptibility gene for rat type 1 diabetes mellitus

Nature Genetics volume 31, pages 391–394 (2002)Cite this article

Abstract

The autoimmune disease type 1 diabetes mellitus (insulin-dependent diabetes mellitus, IDDM) has a multifactorial etiology. So far, the major histocompatibility complex (MHC) is the only major susceptibility locus that has been identified for this disease1 and its animal models2,3. The Komeda diabetes-prone (KDP) rat is a spontaneous animal model of human type 1 diabetes4 in which the major susceptibility locus Iddm/kdp1 accounts, in combination with MHC, for most of the genetic predisposition to diabetes5. Here we report the positional cloning of Iddm/kdp1 and identify a nonsense mutation in Cblb, a member of the Cbl/Sli family of ubiquitin-protein ligases6,7. Lymphocytes of the KDP rat infiltrate into pancreatic islets and several tissues including thyroid gland and kidney, indicating autoimmunity. Similar findings in Cblb-deficient mice are caused by enhanced T-cell activation8,9. Transgenic complementation with wildtype Cblb significantly suppresses development of the KDP phenotype. Thus, Cblb functions as a negative regulator of autoimmunity and Cblb is a major susceptibility gene for type 1 diabetes in the rat. Impairment of the Cblb signaling pathway may contribute to human autoimmune diseases, including type 1 diabetes.

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Figure 1: Genetic and physical mapping of Iddm/kdp1.
Figure 2: Mutation analysis of Cblb in the KDP rat.
Figure 3: Association of Iddm/kdp1 (Cblb) genotype with phenotype in the KDP colony.
Figure 4: Histopathological analysis of animals in the KDP colony.
Figure 5: Rescue of the KDP phenotype by the wildtype Cblb transgene.

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Acknowledgements

We thank T. Miki, Z. Cui and T. Kuramoto for support and advice; M. Namae for help with animal breeding; and T. Hirata, E. Okiyama, M. Fuse, A. Hara, R. Yanobu, S. Kaji, K. Kobayashi, and R. Yagi for technical assistance. This study was supported by Grants-in-Aid for Creative Basic Research, for Scientific Research on Priority Areas and for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, by Scientific Research Grants from the Ministry of Health, Labour and Welfare, Japan, and by grants from Novo Nordisk Pharma (S.S.), and Takeda Science Foundation (N.Y.).

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, 260-8670, Japan

    Norihide Yokoi, He-Yao Wang, Hideki Yano, Kazuki Yasuda & Susumu Seino

  2. Department of Medical Genetics (Novo Nordisk Pharma), Chiba University School of Medicine, Chuo-ku, Chiba, 260-8670, Japan

    Norihide Yokoi & Kazuki Yasuda

  3. Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan

    Kajuro Komeda

  4. Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto

    Kazuhiro Kitada & Tadao Serikawa

  5. Japan,

    Kazuhiro Kitada & Tadao Serikawa

  6. Third Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan

    Yuka Saitoh

  7. Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

    Yutaka Seino

  8. Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo, Japan

    Kazuki Yasuda

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  1. Norihide Yokoi
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  2. Kajuro Komeda
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Correspondence to Susumu Seino.

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Yokoi, N., Komeda, K., Wang, HY. et al. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 31, 391–394 (2002). https://doi.org/10.1038/ng927

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