Diabetologia

, Volume 36, Issue 5, pp 414–422 | Cite as

A mutation (Trp1193→Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance

  • M. Iwanishi
  • T. Haruta
  • Y. Takata
  • O. Ishibashi
  • T. Sasaoka
  • K. Egawa
  • T. Imamura
  • K. Naitou
  • T. Itazu
  • M. Kobayashi
Originals

Summary

We evaluated a 35-year-old diabetic male patient with type A insulin resistance, showing acanthosis nigricans. Insulin binding to the patient's Epstein-Barr-virus transformed lymphocytes was mildly reduced. The maximal insulin-stimulated autophosphorylation of the insulin receptor from the patient's transformed lymphocytes was decreased to 45% of that from the control subjects. On examination, the biological activities of insulin and insulin-like growth factor I in the patient's cultured fibroblasts, insulin sensitivity of amino isobutyric acid uptake and thymidine incorporation was decreased, but insulin-like growth factor I action was normal. The sequence analysis of amplified genomic DNA revealed that the patient was heterozygous for a mutation substituting Leu for Trp at codon 1193 in exon 20 of the insulin receptor gene. The patient's mother and sister were also heterozygous for a mutation in the insulin receptor gene that substituted Leu for Trp1193 in the Β subunit of the receptor. Therefore, the mutation causes insulin resistance in a dominant fashion. They were less hyperglycaemic and more hyperinsulinaemic than the proband after glucose loading. The mother had diabetes mellitus but did not show acanthosis nigricans, while the sister did not have diabetes and showed acanthosis nigricans. These results suggest that this mutation causes defective tyrosine kinase activity of the insulin receptor, which results in insulin resistance. Insulin action and phenotypic appearance may be mediated by different factors.

Key words

Insulin receptor mutation tyrosine kinase activity 

References

  1. 1.
    Taylor SI, Kadowaki T, Kadowaki H, Accili D, Cama A, McKeon C (1990) Mutations in insulin receptor gene in insulin resistant patients. Diabetes Care 13: 257–279Google Scholar
  2. 2.
    Kobayashi M, Sasaoka T, Takata Y et al. (1988) Insulin resistance by unprocessed insulin proreceptors: point mutation at the cleavage site. Biochem Biophys Res Commun 153: 657–663Google Scholar
  3. 3.
    Kobayashi M, Sugibayashi M, Sasaoka T et al. (1990) Transfection of cDNA with G→T point mutation at the cleavage site of insulin receptors to cos 7 cells. Biochem Biophys Res Commun 167: 1073–1078Google Scholar
  4. 4.
    Takata Y, Kobayashi M, Maegawa H et al. (1986) A primary defect in insulin receptor in a young male patient with insulin resistance. Metabolism 35: 950–955Google Scholar
  5. 5.
    Sasaoka T, Shigeta Y, Takata Y et al. (1989) Binding specificity and intramolecular signal transmission of uncleaved insulin proreceptor in transformed lymphocytes from a patient with extreme insulin resistance. Diabetologia 32: 371–377Google Scholar
  6. 6.
    Sasaoka T, Kobayashi M, Takata Y et al. (1988) Clarification of signaling pathways mediated by insulin and insulin-like growth factor I receptors in fibroblasts from patients with specific defect in insulin receptor. Diabetes 37: 1515–1523Google Scholar
  7. 7.
    Pilch PF, Czech MP (1989) Interaction of cross-linking agents with the insulin effector system of isolated fat cells. J Biol Chem 254: 3375–3381Google Scholar
  8. 8.
    Knight AB, Rechler MM, Romanus JA, Van Obberghen-Schilling EE, Nissley SP (1981) Stimulation of glucose incorporation and amino acid transport by insulin and an insulin-like growth factor in fibroblasts with defective insulin receptors cultured from a patient with leprechaunism. Proc Natl Acad Sci USA 78: 2554–2558Google Scholar
  9. 9.
    Flier JS, Usher P, Moses AC (1986) Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. Proc Natl Acad Sci USA 83: 664–668Google Scholar
  10. 10.
    Chomczynsky P, Sacci N (1987) Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159Google Scholar
  11. 11.
    Thomas PS (1980) Hybridization of denatured RNA and DNA fragments transfered to nitrocellulose. Proc Natl Acad Sci USA 77: 5201–5205Google Scholar
  12. 12.
    Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning. A laboratory manual, 2nd ed, Vol.2. Cold Spring Harbor Laboratory, Cold Spring Harbor, pp 914–923Google Scholar
  13. 13.
    Gubler U, Hoffman BJ (1983) A simple and very efficient method for generating cDNA libraries. Gene 25: 263–269Google Scholar
  14. 14.
    Seino S, Seino M, Bell GI (1990) Human insulin-receptor gene partial sequence and amplification of exons by polymerase chain reaction. Diabetes 39: 123–128Google Scholar
  15. 15.
    Ebina Y, Ellis L, Jarnagin K et al. (1985) The human insulin receptor cDNA: the structure basis for hormone-activated trans-membrane signalling. Cell 40: 747–758Google Scholar
  16. 16.
    Accili D, Frapier C, Mosthaf L et al. (1989) 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: 2509–2517Google Scholar
  17. 17.
    Kadowaki T, Kadowaki H, Rechler MM et al. (1990) Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest 86: 254–264Google Scholar
  18. 18.
    Kadowaki T, Kadowaki H, Accili D et al. (1991) Substitution of arginine for histidine at position 209 in the α-subunit of the human insulin receptor. J Biol Chem 266: 21224–21231Google Scholar
  19. 19.
    Maassen JA, Vorm ER, Zon GC et al. (1991) A leucine to proline mutation at position 233 in the insulin receptor inhibits cleavage of the proreceptor and transport to the cell surface. Biochemistry 30: 10778–10783Google Scholar
  20. 20.
    Kadowaki H, Kadowaki T, Cama A et al. (1990) Mutagenesis of lysine 460 in the human insulin receptor. J Biol Chem 265: 21285–21296Google Scholar
  21. 21.
    Kusari J, Takata Y, Hatada E et al. (1991) Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles. J Biol Chem 266: 5260–5267Google Scholar
  22. 22.
    Yamamoto R, Koshio O, Tobe K et al. (1990) Phosphorylation state and biological function of a mutant human insulin receptor Val996. J Biol Chem 265: 14777–14783Google Scholar
  23. 23.
    Moller DE, Yokota A, White MF et al. (1990) A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. J Biol Chem 265: 14979–14985Google Scholar
  24. 24.
    Cama A, Quon MJ, de la Luz Sierra M, Taylor SI (1992) Substitution of isoleucine for methionine at position 1153 in the Β-subunit of the human insulin receptor. J Biol Chem 267: 8383–8389Google Scholar
  25. 25.
    Moller DE, Benecke H, Flier JS (1991) Biologic activities of naturally occurring human insulin receptor mutations. J Biol Chem 266: 10995–11001Google Scholar
  26. 26.
    Hanks SK, Quinn AM (1991) Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Meth Enzymol 200: 38–62Google Scholar
  27. 27.
    O'Hare T, Pilch PF (1988) Separation and characterization of three insulin receptor species that differ in subunit composition. Biochemistry 27: 5693–5700Google Scholar
  28. 28.
    Moller DE, Yokota A, Ginsberg-Fellner F, Flier JS (1990) Functional properties of a naturally occurring Trp1200→Ser1200 mutation of the insulin receptor. Mol Endocrinol 4: 1183–1191Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • M. Iwanishi
    • 1
  • T. Haruta
    • 1
  • Y. Takata
    • 1
  • O. Ishibashi
    • 1
  • T. Sasaoka
    • 1
  • K. Egawa
    • 1
  • T. Imamura
    • 1
  • K. Naitou
    • 2
  • T. Itazu
    • 2
  • M. Kobayashi
    • 1
  1. 1.First Department of MedicineToyama Medical and Pharmaceutical UniversityToyamaJapan
  2. 2.Division of Endocrinology and MetabolismNagoya Second Red Cross HospitalNagoyaJapan

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