Genetics of the insulin receptor defect in a patient with extreme insulin resistance

A patient with extreme insulin resistance (leprechaun/Ark-1) had an 80-90% decrease in the number of insulin receptors on her circulating monocytes. In contrast, while a normal number of insulin receptors was expressed on the surface of Epstein-Barr (EB) virus-transformed lymphocytes from the patient, the receptors had decreased sensitivity to changes in temperature and pH. The father, who had a moderate degree of insulin resistance, resembled the patient in that his monocytes had a 60-80% decrease in the number of insulin receptors. Binding to the father's EB virus-transformed lymphocytes was normal. The mother was normally sensitive to insulin and had a normal number of insulin receptors on her circulating monocytes. In contrast, insulin receptors on the mother's EB virus-transformed lymphocytes were qualitatively abnormal, closely resembling the daughter's cultured cells. These observations suggest that each parent has transmitted a different genetic defect to the patient. When both mutations coexist in the same individual, they fail to complement, but, rather, result in extreme insulin resistance.