Mutations in the Insulin Receptor Gene in Patients with Genetic Syndromes of Insulin Resistance

  • Simeon I. Taylor
  • Domenico Accili
  • Alessandro Cama
  • Hiroko Kadowaki
  • Takashi Kadowaki
  • Eiichi Imano
  • Maria de la Luz Sierra
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 293)

Abstract

Insulin resistance contributes importantly to the pathogenesis of noninsulin-depedendent diabetes mellitus (NIDDM) (1, 2). Furthermore, in longitudinal studies, insulin resistance has been shown to be among the best predictors of future development of NIDDM (3,4). Therefore, we have focused upon genetic causes of insulin resistance in the hope that this will help us to identify genetic factors that predispose to the development of NIDDM. Because of the central role of the insulin receptor in mediating the first step in insulin action (5), we have begun by examining the insulin receptor gene in insulin resistant patients. We have selected patients who manifest an extreme degree of insulin resistance in the hope that the severe insulin resistance would be associated with major biochemical defects, thereby simplifying the task of identifying the molecular defect. In this review, we will summarize the mutations that have been identified in the insulin receptor genes of patients with extreme insulin resistance. Interestingly, multiple different types of mutations have been identified (5). In addition to elucidating the molecular genetics of human insulin resistance, these studies have begun to give new insights into structure-function relationships of the insulin receptor protein.

Keywords

Insulin Resistance Insulin Receptor Insulin Binding Acanthosis Nigricans Severe Insulin Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Reaven GM: Role of insulin resistance in human disease. Diabetes 37:1595–1607, 1988.PubMedCrossRefGoogle Scholar
  2. 2.
    DeFronzo RA: Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667–687, 1988.PubMedGoogle Scholar
  3. 3.
    Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennet PH. The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med. 319: 1500–1506,1988.PubMedCrossRefGoogle Scholar
  4. 4.
    Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med. 318:1217–1225,1988.PubMedCrossRefGoogle Scholar
  5. 5.
    Taylor SI, Kadowaki T, Kadowaki H, Accili D, Cama A, McKeon C: Mutations in insulin-receptor gene in insulin-resistant patients. Diabetes Care 13:257–279, 1990.PubMedCrossRefGoogle Scholar
  6. 6.
    Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW: Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes. Diabetes 34:101–107, 1985.PubMedCrossRefGoogle Scholar
  7. 7.
    Fradkin JE, Eastman RC, Lesniak MA, Roth, J: Specificity spillover at the hormone receptor-exploring its role in human disease. N. Engl. J. Med. 320:640–645, 1989.PubMedCrossRefGoogle Scholar
  8. 8.
    Taylor SI, Dons RF, Hernandez E, Roth J, Gorden P: Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Intern Med 97:851–855, 1982.PubMedGoogle Scholar
  9. 9.
    Barbieri RL, Ryan KJ: Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 147:90–101, 1983.PubMedGoogle Scholar
  10. 10.
    Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J: The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 294:739–745, 1976.PubMedCrossRefGoogle Scholar
  11. 11.
    Rossini AA, Cahill GF, Jr.: Lipoatrophic diabetes in Endocrinology , De Groot LJ, Cahill GF, Jr., Martini L et al. (Eds.) Volume 2, pp. 1093–1097. New York; Grune & Stratton.Google Scholar
  12. 12.
    Rosenberg AM, Haworth JC, Degroot GW, et al: A case of leprechaunism with severe hyperinsulinemia. Am J Dis Child 134:170–175, 1980.PubMedGoogle Scholar
  13. 13.
    Rabson SM, Mendenhall EN: Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus. Amer J. Clin Path ,26:283– ,1956.Google Scholar
  14. 14.
    West RJ, Leonard JV: Familiar insulin resistance with pineal hyperplasia: metabolic studies and effects of hypophysectomy. Arch Dis Child 55:619–621, 1980.PubMedCrossRefGoogle Scholar
  15. 15.
    Yang-Feng TL, Francke U, Ullrich A: Gene for human insulin receptor: localization to site on chromosome 19 involved in pre-B-cell leukemia. Science 228:728–731, 1985.PubMedCrossRefGoogle Scholar
  16. 16.
    DeMeyts, P., J.-L. Gu, R.M. Shymko, B.E. Kaplan, G.I. Bell, J. Whittaker: Identification of a ligand binding region of the human insulin receptor encoded by second exon of the gene. Molecular Endocrinology ,4:409–416, 1990.CrossRefGoogle Scholar
  17. 17.
    Ullrich A, Bell JR, Chen EY, Herrera R, Petruzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J: Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761, 1985.PubMedCrossRefGoogle Scholar
  18. 18.
    Ebina, Y., Ellis, L., Jarnagin, K., Edery, M., Graf, L., Clauser, E., Ou, J.H., Masiarz F., Kan, Y.W., Goldfine, I.D., Roth, R.A., and Rutter, W.J. : The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell 40:747–758, 1985.PubMedCrossRefGoogle Scholar
  19. 19.
    Frias I, Waugh SM: Probing the a-a subunit interface region in the insulin receptor, location of interhalf disulfide(s). Diabetes 38 (suppl. 2): 60A (Abstract #238), 1989.Google Scholar
  20. 20.
    Seino S, Bell GI: Alternative splicing of human insulin receptor messenger RNA. Biochem Biophys Res Commun 159:312–316, 1989.PubMedCrossRefGoogle Scholar
  21. 21.
    Moller DE, Yokota A, Caro JF, Flier JS: Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. Mol. Endocrinol. 3:1263–1269,1989.PubMedCrossRefGoogle Scholar
  22. 22.
    Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, McClain DA: Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J 9:2409–2413, 1990.PubMedGoogle Scholar
  23. 23.
    White MF, Shoelson SE, Keutmann H, Kahn CR: A cascade of tyrosine autophosphorylation in the beta-subunit activates the phosphotransferase of the insulin receptor. J Biol Chem 263:2969–2980, 1988.PubMedGoogle Scholar
  24. 24.
    White MF, Livingston JN, Backer JM, Lauris V, Dull TJ, Ullrich A, Kahn CR: Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell 54:641–649, 1988.PubMedCrossRefGoogle Scholar
  25. 25.
    Tornqvist HE, Gunsalus JR, Nemenoff RA, Frackelton HR, Pierce MW, Avruch J: Identification of the insulin receptor tyrosine residues undergoing insulin-stimulated phosphorylation in intact rat hepatoma cells. J Biol Chem 263:350–359, 1988.PubMedGoogle Scholar
  26. 26.
    Hanks SK, Quinn AM, Hunter T: The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42–52, 1988.PubMedCrossRefGoogle Scholar
  27. 27.
    Pilch PF, Czech MP: Interaction of cross-linking agents with the insulin effector system of isolated fat cells. Covalent linkage of 125I-insulin to a plasma membrane receptor protein of 140,000 daltons. J Biol Chem 254:3375–3381, 1979.PubMedGoogle Scholar
  28. 28.
    Grunfeld C, Shigenaga JK, Ramachandran J: Urea treatment allows dithiothreitol to release the binding subunit of the insulin receptor from the cell membrane: implications for the structural organization of the insulin receptor. Biochem Biophys Res Commun 133:389–396, 1985.PubMedCrossRefGoogle Scholar
  29. 29.
    Kasuga M, Karlsson FA, Kahn CR: Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185–187, 1982.PubMedCrossRefGoogle Scholar
  30. 30.
    Kasuga M, Zick Y, Blithe DL, Crettaz M, Kahn CR: Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system. Nature 298:667–669, 1982.PubMedCrossRefGoogle Scholar
  31. 32.
    Chou CK, Dull TJ, Russell DS, Gherzi R, Lebwohl D, Ullrich A: Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin. J Biol Chem 262:1842–18447, 1987.PubMedGoogle Scholar
  32. 33.
    Ebina Y, Araki E, Taira M, Shimada F, Mori M, Craik CS, Siddle K, Pierce SB, Roth RA, Rutter WJ: Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin-and antibody-stimulated glucose uptake and receptor kinase activity. Proc Natl Acad Sci USA 84:704–708, 1987.PubMedCrossRefGoogle Scholar
  33. 34.
    McClain DA, Maegawa H, Lee J, Dull TJ, Ullrich A, Olefsky JM: A mutant insulin receptor with defective tyrosine kinase displays no biologic activity and does not undergo endocytosis. J Biol Chem 262:14663–14671, 1987.PubMedGoogle Scholar
  34. 35.
    Hedo JA, Kahn CR, Hayashi M, Yamada Km, Kasuga M: Biosynthesis and glycosylation of the insulin receptor. Evidence for a single polypeptide precursor of the two major subunits. J Biol Chem 258:10020–10026,1983.PubMedGoogle Scholar
  35. 36.
    Deutsch PJ, Wan CF, Rosen OM, Rubin CS: Latent insulin receptors and possible receptor precursors in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 80:133–136, 1983.PubMedCrossRefGoogle Scholar
  36. 37.
    Jacobs SJ, Kull FCJ, Cuatrecasas P: Monensin blocks the maturation of receptors for insulin and somatomedin C: Identification of receptor precursors. Proc Natl Acad Sci USA 80:1228–1231, 1983.PubMedCrossRefGoogle Scholar
  37. 38.
    Hedo JA, Kasuga M, Van Obberghen E, Roth J, Kahn CR: Direct demonstration of glycosylation of insulin receptor subunits by biosynthetic and external labeling: evidence for heterogeneity. Proc Natl Acad Sci USA 78:4791–4795, 1981.PubMedCrossRefGoogle Scholar
  38. 39.
    Herzberg VL, Grigorescu F, Edge AS, Spiro RG, Kahn CR: Characterization of insulin receptor carbohydrate by comparison of chemical and enzymatic deglycosylation. Biochem Biophys Res Commun 129:789–796, 1985.PubMedCrossRefGoogle Scholar
  39. 40.
    Collier E, Gorden P: The insulin receptor contains O-linked oligosaccharide. Diabetes 38 (suppl. 2) :178A (Abstract #686), 1989.Google Scholar
  40. 41.
    Hedo JA, Collier E, Watkinson A: Myristyl and palmityl acylation of the insulin receptor. J Biol Chem 262:954–957, 1987.PubMedGoogle Scholar
  41. 42.
    Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47, 1986.PubMedCrossRefGoogle Scholar
  42. 43.
    Kadowaki T, Bevins CL, Cama A, Ojamaa K, Marcus-Samuels B, Kadowaki H, Beitz L, McKeon C, Taylor SI: Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. Science 240:787–790, 1988.PubMedCrossRefGoogle Scholar
  43. 44.
    Kadowaki T, Kadowaki H, Taylor SI: A nonsense mutation causing decreased levels of insulin receptor mRNA: Detection by a simplified technique for direct sequencing of genomic DNA amplified by polymerase chain reaction. Proc Natl Acad Sci USA 87:658–662, 1990.PubMedCrossRefGoogle Scholar
  44. 45.
    Kadowaki T, Kadowaki H, Rechler MM, Serrano-Rios M, Roth J, Gorden P, Taylor SI: Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest 86:254–264, 1990.PubMedCrossRefGoogle Scholar
  45. 46.
    Accili D, Frapier C, Mosthaf L, McKeon C, Elbein S, Permutt MA, Ramos E, Lander E, Ullrich A, Taylor SI: A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin resistant diabetes. EMBO J 8:2509–2517, 1989.PubMedGoogle Scholar
  46. 47.
    Kadowaki T, Kadowaki H, Accili D, Taylor SI: Substitution of lysine for asparagine-15 in the human insulin receptor impairs intracellular transport of the receptor to the cell surface and decreases the affinity of insulin binding, J. Biol Chem. ,265: 19143–19150, 1990.Google Scholar
  47. 48.
    Yoshimasa Y, Seino S, Whittaker J, Kakehi T, Kosaki A, Kuzuya H, Imura I, Bell GI, Steiner DF: Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing. Science 240:784–787, 1988.PubMedCrossRefGoogle Scholar
  48. 49.
    Kobayashi M, Sasaoka T, Takata Y, Ishibashi O, Sugibayashi M, Shigeta Y, Hisatomi A, Nakamura E, Tamaki M, Teraoka H: Insulin resistance by unprocessed insulin proreceptors point mutation at the cleavage site. Biochem Biophys Res Commun 153:657–663, 1988.PubMedCrossRefGoogle Scholar
  49. 50.
    Kakehi T, Hisatomi A, Kuzuya H, Yoshimasa Y, Okamoto M, Yamada K, Nishimura H, Kosaki A, Nawata H, Umeda F, Ibayashi H, Imura H: Defective processing of insulin receptor precursor in cultured lymphocytes from a patient with extreme insulin resistance. J Clin Invest 81:2020–2022,1988.PubMedCrossRefGoogle Scholar
  50. 51.
    Kobayashi M, Sasaoka T, Takata Y, Hisatomi A, Shigeta Y: Insulin resistance by uncleaved insulin proreceptor. Emergence of binding site by trypsin. Diabetes 37:653, 1988.PubMedCrossRefGoogle Scholar
  51. 52.
    Accili D, Mosthaf L, Ullrich A, Taylor S.I. (1990) A mutation in the extracellular domain of the insulin receptor impairs the ability of insulin to stimulate receptor autophosphorylation. J Biol Chem 266:in press, 1990.Google Scholar
  52. 53.
    Odawara M, Kadowaki T, Yamamoto R, Shibasaki Y, Tobe K, Accili D, Bevins C, Mikami Y, Matsuura N, Akanuma Y, Takaku F, Taylor SI, Kasuga M: Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor. Science 245:66–68, 1989.PubMedCrossRefGoogle Scholar
  53. 54.
    Moller DE, Flier JS: Detection of an alteration in the insulin-receptor gene in a patient with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (type A insulin resistance). N Engl J Med 319:1526–1529, 1988.PubMedCrossRefGoogle Scholar
  54. 55.
    Moller DE, Yokota A, Ginsberg-Fellner F, Flier JS: Funtional properties of a naturally occurring Trp1200→Ser1200 mutation of the insulin receptor. Mol Endocrinol 4:1183–1191, 1990.PubMedCrossRefGoogle Scholar
  55. 56.
    Moller DE, Yokota A, White MF, Pazianos AG, Flier JS: A naturally occurring mutation of insulin receptor Ala1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. J Biol Chem 265:14979–14985, 1990.PubMedGoogle Scholar
  56. 57.
    Cama A, Sierra M, Ottini L, Imperato J, Taylor SI: A mutation in the tyrosine kinase domain of the insulin receptor causing insulin resistance in an obese woman. Diabetes ,in press (abstract), 1991.Google Scholar
  57. 58.
    Cama A, Sierra M, Ottini L, Taylor SI: A mutation at Ala1135 in one allele of the insulin receptor gene of a patient with type A extreme insulin resistance. Endocrinology ,in press (abstract), 1991.Google Scholar
  58. 59.
    Kadowaki H, Kadowaki T, Cama A, Marcus-Samuels B, Rovira A, Bevins C, Taylor SI: Mutagenesis of lysine-460 in the human insulin receptor: effects upon receptor recycling and site-site interactions among binding sites, J. Biol. Chem. ,265: in press, 1990.Google Scholar
  59. 60.
    Klinkhamer M, Groen NA, van der Zon GCM, Lindhout D, Sandkuyl LA, Krans HM, Möller W, Maassen JA: A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance. EMBO J 8:2503–2507, 1989.PubMedGoogle Scholar
  60. 61.
    Shimada F, Taira M, Suzuki Y, Hashimoto N, Nozaki O, Taira M, Tatibana M, Ebina Y, Tawata M, Onaya T, Makino H, Yoshida S: Insulin-resistant diabetes associated with partial deletion of insulin-receptor gene. Lancet 335:1179–1181, 1990.PubMedCrossRefGoogle Scholar
  61. 62.
    Taira M, Taira M, Hashimoto N, Shimada F, Suzuki Y, Kanatsuka A, Nakamura F, Ebina Y, Tatibana M, Makino H, Yoshida S: Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor. Science 245:63–66, 1989.PubMedCrossRefGoogle Scholar
  62. 63.
    Ojamaa K, Hedo JA, Roberts CT Jr, Moncada VY, Gorden P, Ullrich A, Taylor SI: Defects in human insulin receptor gene expression. Mol Endocrinol 2:242–247, 1988.PubMedCrossRefGoogle Scholar
  63. 64.
    Taylor SI, Samuels B, Roth J, Kasuga M, Hedo JA, Gorden P, Brasel DE, Pokora T, Engel RR: Decreased insulin binding in cultured lymphocytes from two patients with extreme insulin resistance. J Clin Endocrinol Metab 54:919–930, 1982.PubMedCrossRefGoogle Scholar
  64. 65.
    Imano E, Kadowaki H, Kadowaki T, Iwama N, Watarai T, Kawamori R, Kamada T, Taylor SI: Two patients with insulin resistance due to decreased levels of insulin receptor mRNA. Diabetes ,in press (abstract), 1991.Google Scholar
  65. 66.
    Barnes ND, Palumbo PJ, Hayles AB, Folgar H: Insulin resistance, skin changes, and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction. Diabetologia 10:285–289, 1974.PubMedGoogle Scholar
  66. 67.
    Hedo JA, Moncada VY, Taylor SI: Insulin receptor biosynthesis in cultured lymphocytes from insulin-resistant patients. J Clin Invest 76:2355–2361, 1985.PubMedCrossRefGoogle Scholar
  67. 68.
    Kadowaki H, Kadowaki T, Taylor SI: A mutation in the cysteine-rich domain of the insulin receptor that impairs post-translational processing and transport of receptors to the plasma membrane. Diabetes ,in press (abstract), 1991.Google Scholar
  68. 69.
    Taylor SI, Roth J, Blizzard RM, Elders MJ: Qualitative abnormalities in insulin binding in a patient with extreme insulin resistance: Decreased sensitivity to alterations in temperature and pH. Proc Natl Acad Sci USA 78:7157–7161, 1981.PubMedCrossRefGoogle Scholar
  69. 70.
    Taylor SI, Marcus-Samuels B, Ryan-Young J, Leventhal S, Elders MJ: Genetics of the insulin receptor defect in a patient with extreme insulin resistance. J Clin Endocrinol Metab 62:1130–1135, 1986.PubMedCrossRefGoogle Scholar
  70. 71.
    Davis CG, Goldstein JL, Sudhof TC, Anderson RG. Russell DW, Brown MS: Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. Nature 326:760– 765,1987.PubMedCrossRefGoogle Scholar
  71. 72.
    Moller DE, Yokota A, Flier JS: Normal insulin-receptor cDNA sequence in Pima Indians with NIDDM. Diabetes 38:1496–1500, 1989.PubMedCrossRefGoogle Scholar
  72. 73.
    Cama A, Patterson A, Kadowaki T, Siegel G, D’Ambrosio D, Lillioja S, Roth J, Taylor SI: Cloning of insulin receptor cDNA from an insulin resistant Pima Indian. J Clin Endocrinol Metab 70:1155–1161, 1990.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Simeon I. Taylor
    • 1
  • Domenico Accili
    • 1
  • Alessandro Cama
    • 1
  • Hiroko Kadowaki
    • 1
  • Takashi Kadowaki
    • 1
  • Eiichi Imano
    • 1
  • Maria de la Luz Sierra
    • 1
  1. 1.Diabetes Branch National Institute of Diabetes, Digestive, and Kidney DiseasesNational Institutes of HealthBethesdaUSA

Personalised recommendations