Receptors for insulinlike growth factor I are defective in fibroblasts cultured from a patient with leprechaunism.

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Abstract

We previously have demonstrated that fibroblasts from a patient with leprechaunism exhibited markedly decreased insulin binding to insulin receptors and that the ability of insulin to stimulate glucose incorporation in the patient's cells was greatly impaired. In addition, the insulinlike growth factor, multiplication-stimulating activity (MSA), also exhibited an impaired ability to stimulate glucose incorporation in the patient's fibroblasts, although in normal fibroblasts this response appears to be mediated by an insulinlike growth factor receptor. The present study examines 125I-labeled insulinlike growth factor I (IGF-I) binding to patient's and control fibroblasts. 125I-labeled IGF-I binds to a specific IGF-I receptor in normal fibroblasts. At steady state, binding was inhibited by unlabeled IGF-I, IGF-II, MSA III-2, MSA II, insulin, and proinsulin, in order of potency, but not by high concentrations of epidermal growth factor and human growth hormone, chemically unrelated polypeptides 125I-labeled IGF-I binding to patient's cells was decreased by approximately 75%, whereas binding of epidermal growth factor to its cell surface receptors was unaffected. Computer curve-fitting of untransformed equilibrium binding data suggests that the decreased binding resulted from a decreased Ka for IGF-I. The ability of the patient's IGF-I receptor to recognize insulin also appears to be altered. Impaired IGF-I binding by the leprechaun patient's fibroblasts may contribute to the abnormal biological response to insulinlike growth factors observed in vitro and to the in utero growth retardation.

Authors

E E Van Obberghen-Schilling, M M Rechler, J A Romanus, A B Knight, S P Nissley, R E Humbel