Nature Genetics
31, 391 - 394 (2002)
Published online: 15 July 2002; | doi:10.1038/ng927
Cblb is a major susceptibility gene for rat type 1 diabetes mellitusNorihide Yokoi1, 2, Kajuro Komeda3, He-Yao Wang1, Hideki Yano1, Kazuhiro Kitada4, Yuka Saitoh5, Yutaka Seino6, Kazuki Yasuda1, 2, 7, Tadao Serikawa4
& Susumu Seino11
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan. 2
Department of Medical Genetics (Novo Nordisk Pharma), Chiba University School of Medicine, Chuo-ku, Chiba 260-8670, Japan. 3
Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan. 4
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. 5
Third Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan. 6
Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. 7
Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo, Japan.
Correspondence should be addressed to Susumu Seino seino@med.m.chiba-u.ac.jpThe 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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