0021 -972X/91/7304-0894$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 73, No. 4 Printed in U.S.A.
A Mutation in the Tyrosine Kinase Domain of the Insulin Receptor Associated with Insulin Resistance in an Obese Woman* ALESSANDRO CAMA, MARIA DE LA LUZ SIERRA, LAURA OTTINI, TAKASHI KADOWAKI, PHILLIP GORDEN, JULIANNE IMPERATO-McGINLEY, AND SIMEON I. TAYLOR Diabetes Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health (A.C., M.D.L.L.S., L.O., T.K., P.G., S.I.T.), Bethesda, Maryland 20892; and the Department of Pediatrics, New York Hospital, Cornell University School of Medicine (J.I.-M.), New York, New York 10021
1158, 1162, and 1163. Studies of the mutant receptor expressed in NIH-3T3 cells demonstrated that the Ile1153-mutation impairs the ability of insulin to stimulate autophosphorylation of solubilized insulin receptors. In addition, the mutation impairs the ability of insulin to stimuate receptor tyrosine kinase activity to phosphorylate an artificial substrate [poly(Glu-Tyr)]. It seems likely that this defect in receptor tyrosine kinase activity explains the defect in the ability of the patient's insulin receptors to mediate insulin action in vivo. Furthermore, this patient provides a paradigm in which genetic factors act in concert with other risk factors, such as obesity, to cause clinically important insulin resistance. (J Clin Endocrinol Metab 73: 894-901,1991)
ABSTRACT. Insulin resistance is frequently associated with acanthosis nigricans and hyperandrogenism. In patients with type A insulin resistance, this has been shown to be due to genetic defects in insulin receptor function. However, other patients with a similar clinical syndrome have been reported to have a variant of this syndrome, in which assays of insulin receptor function were normal. We have sequenced a portion of the insulin receptor gene in one such patient, a 29-yr-old woman with obesity and insulin resistance. The patient is heterozygous for a mutation substituting isoleucine for methionine at position 1153. Met1153 is located in the intracellular domain of the receptor near the cluster of tyrosine phosphorylation sites at positions
I
NSULIN resistance is frequently associated with hyperandrogenism and acanthosis nigricans in young women with a wide variety of causes of insulin resistance. In some women the primary cause of disease is a mutation in the insulin receptor gene (1-9). Hyperandrogenism has also been described in premenopausal women who develop extreme insulin resistance as a consequence of autoantibodies directed against the insulin receptor (10). Indeed, this close association, regardless of the biochemical cause of insulin resistance, has led to the hypothesis that hyperandrogenism and acanthosis nigricans are consequences of the insulin-resistant state. Some obese patients present a similar clinical syndrome, although the cause of insulin resistance has not been elucidated (11-13). The patient we studied was reported previously as an example of a patient with the syndrome of insulin resistance, hyperandrogenism, and acanthosis nigricans de-
spite having normal levels of insulin binding to circulating monocytes (14, 15); in addition, she is obese. This patient has milder insulin resistance than most of the patients who have previously been described to have mutations in their insulin receptor genes (1, 2, 6, 7, 16, 17). We now demonstrate that she is heterozygous for a mutation in the insulin receptor gene that substitutes isoleucine for Met1153 in the /J-subunit of the receptor. This mutation inhibits insulin receptor tyrosine kinase activity.
Materials and Methods Clinical features of the patient Patient A-6 is a 29-yr-old woman with insulin resistance (14, 15). She presented several features of type A insulin resistance, including acanthosis nigricans and virilization; however, in addition, she is obese (Table 1). The degree of obesity has increased over the years from 114% of ideal body weight at age 15 yr to 151% at age 29 yr. Intriguingly, her insulin resistance has become less severe over time, as judged by the decline in fasting insulin levels from 2.15 nM at age 15 yr to 0.9 nM at age 29 yr. Furthermore, the patient was diabetic, as judged by an oral glucose tolerance test at age 15 yr (2 h glucose, >11 mM;
Received January 18, 1991. Address all correspondence and requests for reprints to: Simeon I. Taylor, M.D., Ph.D., National Insitutes of Health, Building 10, Room 8S-243, Bethesda, Maryland 20892. * This work was supported by the Juvenile Diabetes Foundation (to Ms. Laura Ottini through the Student Summer Research Program).
894
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 00:49 For personal use only. No other uses without permission. . All rights reserved.
INSULIN RECEPTOR TYROSINE KINASE MUTATION
895
TABLE 1. Clinical characteristics of patient A-6 Age (yr)
Testosterone (ng/dL)°
15 16 19 22 29
250 55 21 27
Normal range
15-60
Plasma glucose (mg/dL)" % of ideal BW 114 125 143 151
Fasting
2h
Monocyte binding (%)
Fasting insulin (MU/mLr
81 76 76
205 158 125
7.8
298 275 75
76
123
9.6
125
4-11
Vol. 73, No. 4 Printed in U.S.A.
A Mutation in the Tyrosine Kinase Domain of the Insulin Receptor Associated with Insulin Resistance in an Obese Woman* ALESSANDRO CAMA, MARIA DE LA LUZ SIERRA, LAURA OTTINI, TAKASHI KADOWAKI, PHILLIP GORDEN, JULIANNE IMPERATO-McGINLEY, AND SIMEON I. TAYLOR Diabetes Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health (A.C., M.D.L.L.S., L.O., T.K., P.G., S.I.T.), Bethesda, Maryland 20892; and the Department of Pediatrics, New York Hospital, Cornell University School of Medicine (J.I.-M.), New York, New York 10021
1158, 1162, and 1163. Studies of the mutant receptor expressed in NIH-3T3 cells demonstrated that the Ile1153-mutation impairs the ability of insulin to stimulate autophosphorylation of solubilized insulin receptors. In addition, the mutation impairs the ability of insulin to stimuate receptor tyrosine kinase activity to phosphorylate an artificial substrate [poly(Glu-Tyr)]. It seems likely that this defect in receptor tyrosine kinase activity explains the defect in the ability of the patient's insulin receptors to mediate insulin action in vivo. Furthermore, this patient provides a paradigm in which genetic factors act in concert with other risk factors, such as obesity, to cause clinically important insulin resistance. (J Clin Endocrinol Metab 73: 894-901,1991)
ABSTRACT. Insulin resistance is frequently associated with acanthosis nigricans and hyperandrogenism. In patients with type A insulin resistance, this has been shown to be due to genetic defects in insulin receptor function. However, other patients with a similar clinical syndrome have been reported to have a variant of this syndrome, in which assays of insulin receptor function were normal. We have sequenced a portion of the insulin receptor gene in one such patient, a 29-yr-old woman with obesity and insulin resistance. The patient is heterozygous for a mutation substituting isoleucine for methionine at position 1153. Met1153 is located in the intracellular domain of the receptor near the cluster of tyrosine phosphorylation sites at positions
I
NSULIN resistance is frequently associated with hyperandrogenism and acanthosis nigricans in young women with a wide variety of causes of insulin resistance. In some women the primary cause of disease is a mutation in the insulin receptor gene (1-9). Hyperandrogenism has also been described in premenopausal women who develop extreme insulin resistance as a consequence of autoantibodies directed against the insulin receptor (10). Indeed, this close association, regardless of the biochemical cause of insulin resistance, has led to the hypothesis that hyperandrogenism and acanthosis nigricans are consequences of the insulin-resistant state. Some obese patients present a similar clinical syndrome, although the cause of insulin resistance has not been elucidated (11-13). The patient we studied was reported previously as an example of a patient with the syndrome of insulin resistance, hyperandrogenism, and acanthosis nigricans de-
spite having normal levels of insulin binding to circulating monocytes (14, 15); in addition, she is obese. This patient has milder insulin resistance than most of the patients who have previously been described to have mutations in their insulin receptor genes (1, 2, 6, 7, 16, 17). We now demonstrate that she is heterozygous for a mutation in the insulin receptor gene that substitutes isoleucine for Met1153 in the /J-subunit of the receptor. This mutation inhibits insulin receptor tyrosine kinase activity.
Materials and Methods Clinical features of the patient Patient A-6 is a 29-yr-old woman with insulin resistance (14, 15). She presented several features of type A insulin resistance, including acanthosis nigricans and virilization; however, in addition, she is obese (Table 1). The degree of obesity has increased over the years from 114% of ideal body weight at age 15 yr to 151% at age 29 yr. Intriguingly, her insulin resistance has become less severe over time, as judged by the decline in fasting insulin levels from 2.15 nM at age 15 yr to 0.9 nM at age 29 yr. Furthermore, the patient was diabetic, as judged by an oral glucose tolerance test at age 15 yr (2 h glucose, >11 mM;
Received January 18, 1991. Address all correspondence and requests for reprints to: Simeon I. Taylor, M.D., Ph.D., National Insitutes of Health, Building 10, Room 8S-243, Bethesda, Maryland 20892. * This work was supported by the Juvenile Diabetes Foundation (to Ms. Laura Ottini through the Student Summer Research Program).
894
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 00:49 For personal use only. No other uses without permission. . All rights reserved.
INSULIN RECEPTOR TYROSINE KINASE MUTATION
895
TABLE 1. Clinical characteristics of patient A-6 Age (yr)
Testosterone (ng/dL)°
15 16 19 22 29
250 55 21 27
Normal range
15-60
Plasma glucose (mg/dL)" % of ideal BW 114 125 143 151
Fasting
2h
Monocyte binding (%)
Fasting insulin (MU/mLr
81 76 76
205 158 125
7.8
298 275 75
76
123
9.6
125
4-11
