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. 1989 Sep;8(9):2509–2517. doi: 10.1002/j.1460-2075.1989.tb08388.x

A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.

D Accili 1, C Frapier 1, L Mosthaf 1, C McKeon 1, S C Elbein 1, M A Permutt 1, E Ramos 1, E Lander 1, A Ullrich 1, S I Taylor 1
PMCID: PMC401244  PMID: 2573522

Abstract

Insulin binds to a receptor on the cell surface, thereby triggering a biological response within the target cell. Mutations in the insulin receptor gene can render the cell resistant to the biological action of insulin. We have studied a family in which two sisters have a genetic form of insulin-resistant diabetes mellitus. The technique of homozygosity mapping has been used to demonstrate that the mutation causing diabetes in this consanguineous family is genetically linked to the insulin receptor gene. The two insulin-resistant sisters are homozygous for a mutation encoding substitution of valine for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. Transfection of mutant insulin receptor cDNA into NIH3T3 cells demonstrated that the Val382 mutation impaired post-translational processing and retarded transport of the insulin receptor to the plasma membrane. Thus, the mutation causes insulin resistance by decreasing the number of insulin receptors on the surface of the patients' cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Accili D., Elbein S., McKeon C., Taylor S. I. A new EcoRI polymorphism for the insulin receptor gene. Nucleic Acids Res. 1989 Jan 25;17(2):821–821. doi: 10.1093/nar/17.2.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Araki E., Shimada F., Uzawa H., Mori M., Ebina Y. Characterization of the promoter region of the human insulin receptor gene. Evidence for promoter activity. J Biol Chem. 1987 Nov 25;262(33):16186–16191. [PubMed] [Google Scholar]
  3. Bargmann C. I., Hung M. C., Weinberg R. A. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell. 1986 Jun 6;45(5):649–657. doi: 10.1016/0092-8674(86)90779-8. [DOI] [PubMed] [Google Scholar]
  4. Barnes N. D., Palumbo P. J., Hayles A. B., Folgar H. Insulin resistance, skin changes, and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction. Diabetologia. 1974 Aug;10(4):285–289. doi: 10.1007/BF02627729. [DOI] [PubMed] [Google Scholar]
  5. Brown M. S., Goldstein J. L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. doi: 10.1126/science.3513311. [DOI] [PubMed] [Google Scholar]
  6. Cama A., Marcus-Samuels B., Taylor S. I. Immunological abnormalities in insulin receptors on cultured EBV-transformed lymphocytes from insulin-resistant patient with leprechaunism. Diabetes. 1988 Jul;37(7):982–988. doi: 10.2337/diab.37.7.982. [DOI] [PubMed] [Google Scholar]
  7. Coussens L., Van Beveren C., Smith D., Chen E., Mitchell R. L., Isacke C. M., Verma I. M., Ullrich A. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature. 1986 Mar 20;320(6059):277–280. doi: 10.1038/320277a0. [DOI] [PubMed] [Google Scholar]
  8. Downward J., Yarden Y., Mayes E., Scrace G., Totty N., Stockwell P., Ullrich A., Schlessinger J., Waterfield M. D. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984 Feb 9;307(5951):521–527. doi: 10.1038/307521a0. [DOI] [PubMed] [Google Scholar]
  9. Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E., Ou J. H., Masiarz F., Kan Y. W., Goldfine I. D. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985 Apr;40(4):747–758. doi: 10.1016/0092-8674(85)90334-4. [DOI] [PubMed] [Google Scholar]
  10. Elbein S. C., Corsetti L., Ullrich A., Permutt M. A. Multiple restriction fragment length polymorphisms at the insulin receptor locus: a highly informative marker for linkage analysis. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5223–5227. doi: 10.1073/pnas.83.14.5223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Esser V., Russell D. W. Transport-deficient mutations in the low density lipoprotein receptor. Alterations in the cysteine-rich and cysteine-poor regions of the protein block intracellular transport. J Biol Chem. 1988 Sep 15;263(26):13276–13281. [PubMed] [Google Scholar]
  12. Gething M. J., McCammon K., Sambrook J. Expression of wild-type and mutant forms of influenza hemagglutinin: the role of folding in intracellular transport. Cell. 1986 Sep 12;46(6):939–950. doi: 10.1016/0092-8674(86)90076-0. [DOI] [PubMed] [Google Scholar]
  13. Gubler U., Hoffman B. J. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. doi: 10.1016/0378-1119(83)90230-5. [DOI] [PubMed] [Google Scholar]
  14. Haas I. G., Wabl M. Immunoglobulin heavy chain binding protein. Nature. 1983 Nov 24;306(5941):387–389. doi: 10.1038/306387a0. [DOI] [PubMed] [Google Scholar]
  15. Hampe A., Gobet M., Sherr C. J., Galibert F. Nucleotide sequence of the feline retroviral oncogene v-fms shows unexpected homology with oncogenes encoding tyrosine-specific protein kinases. Proc Natl Acad Sci U S A. 1984 Jan;81(1):85–89. doi: 10.1073/pnas.81.1.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hedo J. A., Kahn C. R., Hayashi M., Yamada K. M., Kasuga M. Biosynthesis and glycosylation of the insulin receptor. Evidence for a single polypeptide precursor of the two major subunits. J Biol Chem. 1983 Aug 25;258(16):10020–10026. [PubMed] [Google Scholar]
  17. Hedo J. A., Moncada V. Y., Taylor S. I. Insulin receptor biosynthesis in cultured lymphocytes from insulin-resistant patients. J Clin Invest. 1985 Dec;76(6):2355–2361. doi: 10.1172/JCI112247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hobbs H. H., Brown M. S., Russell D. W., Davignon J., Goldstein J. L. Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia. N Engl J Med. 1987 Sep 17;317(12):734–737. doi: 10.1056/NEJM198709173171204. [DOI] [PubMed] [Google Scholar]
  19. Kadowaki T., Bevins C. L., Cama A., Ojamaa K., Marcus-Samuels B., Kadowaki H., Beitz L., McKeon C., Taylor S. I. Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. Science. 1988 May 6;240(4853):787–790. doi: 10.1126/science.2834824. [DOI] [PubMed] [Google Scholar]
  20. Kahn C. R., Flier J. S., Bar R. S., Archer J. A., Gorden P., Martin M. M., Roth J. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976 Apr 1;294(14):739–745. doi: 10.1056/NEJM197604012941401. [DOI] [PubMed] [Google Scholar]
  21. Kasuga M., Karlsson F. A., Kahn C. R. Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science. 1982 Jan 8;215(4529):185–187. doi: 10.1126/science.7031900. [DOI] [PubMed] [Google Scholar]
  22. Kim S. K., Wold B. J. Stable reduction of thymidine kinase activity in cells expressing high levels of anti-sense RNA. Cell. 1985 Aug;42(1):129–138. doi: 10.1016/s0092-8674(85)80108-2. [DOI] [PubMed] [Google Scholar]
  23. Kris R. M., Lax I., Gullick W., Waterfield M. D., Ullrich A., Fridkin M., Schlessinger J. Antibodies against a synthetic peptide as a probe for the kinase activity of the avian EGF receptor and v-erbB protein. Cell. 1985 Mar;40(3):619–625. doi: 10.1016/0092-8674(85)90210-7. [DOI] [PubMed] [Google Scholar]
  24. Lander E. S., Botstein D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science. 1987 Jun 19;236(4808):1567–1570. doi: 10.1126/science.2884728. [DOI] [PubMed] [Google Scholar]
  25. Lehrman M. A., Schneider W. J., Brown M. S., Davis C. G., Elhammer A., Russell D. W., Goldstein J. L. The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. J Biol Chem. 1987 Jan 5;262(1):401–410. [PubMed] [Google Scholar]
  26. MORTON N. E. Sequential tests for the detection of linkage. Am J Hum Genet. 1955 Sep;7(3):277–318. [PMC free article] [PubMed] [Google Scholar]
  27. Mamula P. W., Wong K. Y., Maddux B. A., McDonald A. R., Goldfine I. D. Sequence and analysis of promoter region of human insulin-receptor gene. Diabetes. 1988 Sep;37(9):1241–1246. doi: 10.2337/diab.37.9.1241. [DOI] [PubMed] [Google Scholar]
  28. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Moller D. E., Flier J. S. 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. 1988 Dec 8;319(23):1526–1529. doi: 10.1056/NEJM198812083192306. [DOI] [PubMed] [Google Scholar]
  30. Munro S., Pelham H. R. An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell. 1986 Jul 18;46(2):291–300. doi: 10.1016/0092-8674(86)90746-4. [DOI] [PubMed] [Google Scholar]
  31. Myers R. M., Larin Z., Maniatis T. Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA:DNA duplexes. Science. 1985 Dec 13;230(4731):1242–1246. doi: 10.1126/science.4071043. [DOI] [PubMed] [Google Scholar]
  32. Ojamaa K., Hedo J. A., Roberts C. T., Jr, Moncada V. Y., Gorden P., Ullrich A., Taylor S. I. Defects in human insulin receptor gene expression. Mol Endocrinol. 1988 Mar;2(3):242–247. doi: 10.1210/mend-2-3-242. [DOI] [PubMed] [Google Scholar]
  33. Podskalny J., McElduff A., Gorden P. Insulin receptors on Chinese hamster ovary (CHO) cells: altered insulin binding to glycosylation mutants. Biochem Biophys Res Commun. 1984 Nov 30;125(1):70–75. doi: 10.1016/s0006-291x(84)80335-6. [DOI] [PubMed] [Google Scholar]
  34. Riedel H., Dull T. J., Schlessinger J., Ullrich A. A chimaeric receptor allows insulin to stimulate tyrosine kinase activity of epidermal growth factor receptor. Nature. 1986 Nov 6;324(6092):68–70. doi: 10.1038/324068a0. [DOI] [PubMed] [Google Scholar]
  35. Ronnett G. V., Knutson V. P., Kohanski R. A., Simpson T. L., Lane M. D. Role of glycosylation in the processing of newly translated insulin proreceptor in 3T3-L1 adipocytes. J Biol Chem. 1984 Apr 10;259(7):4566–4575. [PubMed] [Google Scholar]
  36. Rosen O. M., Chia G. H., Fung C., Rubin C. S. Tunicamycin-mediated depletion of insulin receptors in 3T3-L1 adipocytes. J Cell Physiol. 1979 Apr;99(1):37–42. doi: 10.1002/jcp.1040990106. [DOI] [PubMed] [Google Scholar]
  37. Roussel M. F., Downing J. R., Rettenmier C. W., Sherr C. J. A point mutation in the extracellular domain of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential. Cell. 1988 Dec 23;55(6):979–988. doi: 10.1016/0092-8674(88)90243-7. [DOI] [PubMed] [Google Scholar]
  38. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  39. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sanna M. A., Bell G. I., Cao A., Pirastu M. Three RFLPs for the insulin receptor gene INSR: EcoRI, Pst I, Hind III. Nucleic Acids Res. 1986 Aug 26;14(16):6776–6776. doi: 10.1093/nar/14.16.6776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Seino S., Seino M., Nishi S., Bell G. I. Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci U S A. 1989 Jan;86(1):114–118. doi: 10.1073/pnas.86.1.114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Simpson D., Crosby R. M., Skopek T. R. A method for specific cloning and sequencing of human hprt cDNA for mutation analysis. Biochem Biophys Res Commun. 1988 Feb 29;151(1):487–492. doi: 10.1016/0006-291x(88)90619-5. [DOI] [PubMed] [Google Scholar]
  43. Tager H., Given B., Baldwin D., Mako M., Markese J., Rubenstein A., Olefsky J., Kobayashi M., Kolterman O., Poucher R. A structurally abnormal insulin causing human diabetes. Nature. 1979 Sep 13;281(5727):122–125. doi: 10.1038/281122a0. [DOI] [PubMed] [Google Scholar]
  44. Taylor S. I. Insulin action and inaction. Clin Res. 1987 Sep;35(5):459–472. [PubMed] [Google Scholar]
  45. Ullrich A., Bell J. R., Chen E. Y., Herrera R., Petruzzelli L. M., Dull T. J., Gray A., Coussens L., Liao Y. C., Tsubokawa M. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. 1985 Feb 28-Mar 6Nature. 313(6005):756–761. doi: 10.1038/313756a0. [DOI] [PubMed] [Google Scholar]
  46. Ullrich A., Gray A., Tam A. W., Yang-Feng T., Tsubokawa M., Collins C., Henzel W., Le Bon T., Kathuria S., Chen E. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 1986 Oct;5(10):2503–2512. doi: 10.1002/j.1460-2075.1986.tb04528.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Woolford J., McAuliffe A., Rohrschneider L. R. Activation of the feline c-fms proto-oncogene: multiple alterations are required to generate a fully transformed phenotype. Cell. 1988 Dec 23;55(6):965–977. doi: 10.1016/0092-8674(88)90242-5. [DOI] [PubMed] [Google Scholar]
  48. Yamamoto T., Bishop R. W., Brown M. S., Goldstein J. L., Russell D. W. Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit. Science. 1986 Jun 6;232(4755):1230–1237. doi: 10.1126/science.3010466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yarden Y., Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–478. doi: 10.1146/annurev.bi.57.070188.002303. [DOI] [PubMed] [Google Scholar]
  50. Yoshimasa Y., Seino S., Whittaker J., Kakehi T., Kosaki A., Kuzuya H., Imura H., Bell G. I., Steiner D. F. Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing. Science. 1988 May 6;240(4853):784–787. doi: 10.1126/science.3283938. [DOI] [PubMed] [Google Scholar]

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