Defects in human insulin receptor gene expression

The insulin receptor plays a central role in mediating the biological actions of insulin. We have used Epstein-Barr virus-transformed lymphocytes (EBV-lymphocytes) to investigate the receptor defects in patients with genetic forms of insulin resistance. Within the normal population, we found a close correlation between the number of insulin receptors on the surface of EBV-lymphocytes and the cellular content of insulin receptor mRNA. In addition, we have used the cloned human insulin receptor cDNA to investigate the nature of the mutations causing the reduction in the number of insulin receptors in EBV-lymphocytes from three insulin resistant patients. One patient with leprechaunism has a marked reduction in the level of receptor mRNA, which probably accounts for the extremely slow rate of receptor biosynthesis measured in this patient’s cells. The remaining two patients with type A extreme insulin resistance are sisters, the products of a consanguineous marriage, who have normal levels of insulin receptor mRNA. We have previously shown that the insulin receptor precursor is synthesized at a normal rate in these patients’ cells, thus suggesting a defect in the posttranslational processing of the receptor or in its translocation to the plasma membrane.