Cblb is a major susceptibility gene for rat type 1 diabetes mellitus
Cblb is a major susceptibility gene for rat type 1 diabetes mellitus
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DOI：
10.1038/ng927
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发表时间：
2002-08-01
期刊：
影响因子：
30.8
通讯作者：
Seino, S
中科院分区：
文献类型：
--
作者：
Yokoi, N;Komeda, K;Seino, S
自身免疫性疾病1型糖尿病（胰岛素依赖型糖尿病，IDDM）具有多因素病因。到目前为止，主要组织相容性复合体（MHC）是唯一的主要易感基因座，已确定为这种疾病1及其动物模型（2，3）。Komeda糖尿病易感（KDP）大鼠是人类1型糖尿病的自发动物模型4，其中主要易感基因座Iddm/kdp 1与MHC结合，是糖尿病遗传易感性的主要原因（5）。在这里，我们报告了Iddm/kdp 1的定位克隆，并鉴定了Cblb中的无义突变，Cblb是泛素蛋白连接酶Cbl/Sli家族的成员（6，7）。KDP大鼠的淋巴细胞浸润到胰岛和包括甲状腺和肾脏在内的几种组织中，表明自身免疫。在Cblb缺陷小鼠中的类似发现是由增强的T细胞活化引起的（8，9）。与野生型Cblb的转基因互补显著抑制KDP表型的发展。因此，Cblb作为自身免疫的负调节剂发挥作用，并且Cblb是大鼠中1型糖尿病的主要易感基因。Cblb信号通路的损伤可能导致人类自身免疫性疾病，包括1型糖尿病。
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 disease 1 and its animal models(2,3). The Komeda diabetes-prone (KDP) rat is a spontaneous animal model of human type 1 diabetes 4 in which the major susceptibility locus Iddm/kdp1 accounts, in combination with MHC, for most of the genetic predisposition to diabetes(5). 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 ligases(6,7). 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 activation(8,9). 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.