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

Nat Genet. 2002 Aug;31(4):391-4. doi: 10.1038/ng927. Epub 2002 Jul 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activated-Leukocyte Cell Adhesion Molecule / genetics
  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Animals, Genetically Modified
  • Autoimmunity / genetics
  • Chromosome Mapping
  • Cloning, Molecular
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Ligases / genetics*
  • Ligases / metabolism*
  • Lymphocyte Activation
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Proto-Oncogene Proteins c-cbl
  • Rats
  • Rats, Mutant Strains
  • Rats, Sprague-Dawley
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Ubiquitin-Protein Ligases*


  • Activated-Leukocyte Cell Adhesion Molecule
  • Adaptor Proteins, Signal Transducing
  • Cblb protein, mouse
  • Cblb protein, rat
  • CBLB protein, human
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Ligases

Associated data

  • GENBANK/AB071283