Cblb is a major susceptibility gene for rat type 1 diabetes mellitus.
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 and its animal models. The Komeda diabetes-prone (KDP) rat is a spontaneous animal model of human type 1 diabetes in which the major susceptibility locus Iddm/kdp1 accounts, in combination with MHC, for most of the genetic predisposition to diabetes. 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. 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. 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.
Yokoi
Norihide
N
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
Komeda
Kajuro
K
Wang
He-Yao
HY
Yano
Hideki
H
Kitada
Kazuhiro
K
Saitoh
Yuka
Y
Seino
Yutaka
Y
Yasuda
Kazuki
K
Serikawa
Tadao
T
Seino
Susumu
S
D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D030801:Animals, Genetically Modified; D015551:Autoimmunity / Q000235:genetics; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D008025:Ligases / Q000235:genetics* / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D050721:Proto-Oncogene Proteins c-cbl; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases
D020410:Activated-Leukocyte Cell Adhesion Molecule; D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; C492213:Cblb protein, rat; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D008025:Ligases