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Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo (R.Y., T.S., K.T., Y.S., T.I., M.O., F.T., M.K.) Hongo, Tokyo 113
the Institute for Diabetes Care and Research, Asahi Life Foundation (R.Y., K.T., O.K., Y.AJ Marunouchi, Tokyo 100
the Department of Pediatrics, School of Medicine, Hokkaido University (Y.M., N.M.) Sapporo 060, Japan
Address requests for reprints to: Dr. Masato Kasuga, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7–3–1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
We report here a defect in tyrosine kinase activity of the insulin receptor from an insulin-resistant patient with acanthosis nigricans using cultured Ebstein-Barr virus (EBV)-transformed B-lymphocytes. As judged by affinity labeling and immunoblotting, the
- and β-subunits of insulin receptors from the patient's lymphocytes exhibited the same mol wt as those from control subjects. Lectin-purified extracts from lymphocytes of the patient and the control subjects containing the same insulin-binding capacity were assayed for autophosphorylation and the ability to phosphorylate histone H2B. The degree of insulin-dependent autophosphorylation and the tyrosine kinase activity of the insulin receptor from the patient's lymphocytes were decreased to 15% and 13%, respectively, in a cell-free system. The insulin-dependent autophsphorylation of the insulin receptor was also impaired in intact EBV lymphocytes from the patient. Consistent with these results, we found that one of this patient's alleles had a mutation in which valine is subtituted for Gly996, the third glycine in the conserved Gly-X-Gly-X-X-Gly motif in the kinase domain. Thus, it seems likely that the defect in tyrosine kinase activity of the insulin receptor cause the insulin resistance in this patient. The EBV lymphocyte can be a good system to detect genetically determined abnormalities in the insulin receptor.
* This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan, a grant for the treatment of intractable disease from the Ministry of Health and Welfare of Japan, a grant from the Sankyo Life Science Foundation, and a grant from Uehara Memorial Foundation.
Received March 24, 1989.
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