Human Molecular Genetics, 2004, Vol. 13, No. 2 171-179
DOI: 10.1093/hmg/ddh020
Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus
1Second Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan, 2Central Laboratory of First Clinical College, China Medical University, Shenyang, People's Republic of China, 3Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama 225-8502, Japan, 4Department of Internal Medicine, Yokohama Seamen's Insurance Hospital, Yokohama 240-8585, Japan, 5Second Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo 060-8648, Japan and 6Virology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Received August 19, 2003; Accepted November 11, 2003
Systemic lupus erythematosus (SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex-type tissue inflammation, most prominently in the kidney. Evidence suggests that genetic factors predisposing to aberrant proliferation/maturation of self-reactive B cells initiate and propagate the disease. In SLE-prone New Zealand Black (NZB) mice and their F1 cross with New Zealand White (NZW) mice, B cell abnormalities can be ascribed mainly to self-reactive CD5+ B1 cells. Our genome-wide scans to search for susceptibility genes for aberrant activation of B1 cells in these mice showed evidence that the gene, Ltk, encoding leukocyte tyrosine kinase (LTK), is a possible candidate. LTK is a receptor-type protein tyrosine kinase, belonging to the insulin receptor superfamily, and is mainly expressed in B lymphocyte precursors and neuronal tissues. Sequence and functional analyses of the gene revealed that NZB has a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PI3K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared with the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE.
* To whom correspondence should be addressed at: Second Department of Pathology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel: +81 358021039; Fax: +81 338133164; Email: sacchi{at}med.juntendo.ac.jp
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