Mutation of the insulin receptor gene can compromise the ability of the receptor to mediate insulin action. A homozygous point mutation that results in the substitution of histidine for arginine 252 in the insulin receptor alpha-subunit has now been identified by polymerase chain reaction and single stranded conformational polymorphism analysis in a 20-yr-old Japanese woman with type A syndrome and severe insulin resistance. The proband’s consanguineous parents (diabetic mother and normal father) and her sister (impaired glucose tolerance), each of whom showed an exaggerated insulin response to an oral glucose load, were heterozygous for this mutation. Her brother showed a normal insulin response and lacked the mutation, as did 50 healthy Japanese control subjects. The chronic sc administration of insulin-like growth factor I (IGF-I) improved the patient’s hyperglycemia and corrected certain metabolic abnormalities over a 9-month period, even though the binding of 125I-labeled IGF-I to her cultured fibroblasts was decreased by 40% relative to that to cells from healthy controls. Studies of the binding of 125I-labeled insulin to the proband’s cultured fibroblasts, to COS-I cells transfected with complementary DNA encoding the mutant insulin receptor, and to partially purified mutant receptors revealed that the Arg252→His mutation decreased both cell surface expression and the affinity for insulin for the receptor. These observations suggest that the homozygous Arg252→His mutation is responsible for the type A insulin resistance of the proband, whereas in the heterozygous state, the mutation results in mild insulin resistance indistinguishable from that observed in noninsulin-dependent diabetes mellitus.
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