| RRC ID |
36
|
| 著者 |
Yokoi N, Komeda K, Wang HY, Yano H, Kitada K, Saitoh Y, Seino Y, Yasuda K, Serikawa T, Seino S.
|
| タイトル |
Cblb is a major susceptibility gene for rat type 1 diabetes mellitus.
|
| ジャーナル |
Nat Genet
|
| Abstract |
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.
|
| 巻・号 |
31(4)
|
| ページ |
391-4
|
| 公開日 |
2002-8-1
|
| DOI |
10.1038/ng927
|
| PII |
ng927
|
| PMID |
12118252
|
| MeSH |
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*
|
| IF |
27.605
|
| 引用数 |
144
|
|
WOS 分野
|
GENETICS & HEREDITY
|
| リソース情報 |
| ラット |
KDP/Tky(strainID=15)
TM/Kyo(strainID=10) |
