2 NATURALLY-OCCURRING MUTATIONS IN THE KINASE DOMAIN OF INSULIN-RECEPTOR ACCELERATE DEGRADATION OF THE INSULIN-RECEPTOR AND IMPAIR THE KINASE-ACTIVITY

We identified two novel heterozygous missense mutations of the insulin receptor gene: the Asp(1179) mutation in one family and the Leu(1193) mutation in two unrelated families with extreme insulin resistance. I n these patients, the number of insulin receptors on the cell surface was found to be markedly decreased by insulin binding and surface labe ling studies in transformed lymphocytes. Insulin binding to the transf ected COS 7 cells and Rat-1 cells with both mutant cDNAs was also decr eased to 5-31% of normal, and the mutant insulin receptors showed a ma rkedly decreased kinase activity. Although biosynthetic labeling studi es revealed that both mutant receptors were synthesized as 190-kDa pro receptors, the degradation of the mutant proreceptors was 2-fold faste r than that of the wild type proreceptors. However, the degradation ra te of the mutant receptors on the cell surface was comparable to that of wild type insulin receptor. These results suggest that the Asp(1179 ) and Leu(1193) mutations in the kinase domain are unique in causing d ecreased insulin receptor number on the cell surface by accelerated in tracellular degradation, and that insulin resistance in these patients is mainly due to the decreased receptor number rather than impaired k inase activity.