Identification of a major gene responsible for type 1 diabetes in the Komeda diabetes-prone rat.

Type 1 diabetes mellitus is an autoimmune disease involving both environmental and genetic factors. Genetic analyses in humans and rodents have shown that the major histocompatibility complex (MHC) is a major genetic factor and that several other genes may be involved in the development of the disease. We performed genetic analysis of type 1 diabetes in a newly established animal model, the Komeda diabetes-prone (KDP) rat, and found that most of the genetic predisposition to diabetes is accounted for by two major susceptibility genes, MHC and Iddm/kdp1. In addition, we identified a nonsense mutation in the Casitas B-lineage lymphoma b (Cblb) gene by positional cloning of Iddm/kdp1. In this paper, I review our positional cloning analysis of Iddm/kdp1 and propose a two-gene model of the development of type 1 diabetes in which two major susceptibility genes, Cblb and MHC, determine autoimmune reaction and tissue specificity to pancreatic beta-cells, respectively.