Genetic forms of severe
insulin resistance are often characterized by alterations in binding and/or
kinase properties of the
insulin receptor. To evaluate whether alterations in
insulin receptor kinase of erythrocytes can be used as
genetic markers, we studied patients with two apparently inherited conditions of severe
insulin resistance (
leprechaunism and the type A syndrome of
insulin resistance) and their families. In the two propositi, [125I]
insulin binding to intact erythrocytes was decreased by 64% and 45%, respectively. This was primarily due to a decrease in receptor number and was found in intact cells and solubilization of the receptors. Similar
insulin binding defects were found on monocytes.
Insulin-stimulated
tyrosine kinase activity of the solubilized receptor from erythrocytes was also decreased and to a similar extent as binding. Parents of neither patient had clinical manifestations of
leprechaunism or the type A syndrome. Furthermore, no alterations in
insulin receptor binding or
kinase activity were found in erythrocytes from the mothers.
Insulin binding in the father of the type A patient was also normal, whereas the father of the leprechaun had decreased receptor affinity. Receptors extracted from the both fathers' cells had a 40-60% decrease in maximal
insulin-stimulated phosphorylation and significant rightward shifts of the
insulin dose-response curves (ED50, 141 and 42 ng/mL, respectively; control ED50, 16 ng/mL). The finding of biochemical defects in
insulin receptor kinase activity in clinically unaffected parents of patients suggests that these alterations may be useful
genetic markers and more sensitive than
insulin binding studies for studying pattern of inheritance of these diseases.