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J Clin Invest. 1985 July; 76(1): 378–380.
PMCID: PMC423787

Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia.

Abstract

Familial hyperproinsulinemia is characterized by the accumulation of proinsulin-like material (PLM) in the plasma of affected patients. This disorder is inherited in an autosomal dominant fashion. The accumulation of PLM is thought to be due to the impaired conversion of proinsulin to insulin. Although PLM has been suggested to have an amino acid substitution, it has been impossible to locate and identify a substituted amino acid, due to the difficulty in isolating sufficient amounts of PLM from plasma samples. Therefore, we analyzed leukocyte DNA from one member of a proinsulinemic family, and we found a point mutation that changed guanine to adenine in the insulin gene. This transition implies that a substitution of histidine for arginine has occurred at amino acid position 65. Furthermore, it indicates that arginine at 65 is essential for the conversion of proinsulin to insulin. Our results suggest a novel mechanism by which disease can be incurred: a heritable disorder can result from a posttranslational processing abnormality caused by a point mutation.

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Selected References

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  • Gabbay KH, DeLuca K, Fisher JN, Jr, Mako ME, Rubenstein AH. Familial hyperproinsulinemia. An autosomal dominant defect. N Engl J Med. 1976 Apr 22;294(17):911–915. [PubMed]
  • Gabbay KH, Bergenstal RM, Wolff J, Mako ME, Rubenstein AH. Familial hyperproinsulinemia: partial characterization of circulating proinsulin-like material. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2881–2885. [PubMed]
  • Gruppuso PA, Gorden P, Kahn CR, Cornblath M, Zeller WP, Schwartz R. Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin. N Engl J Med. 1984 Sep 6;311(10):629–634. [PubMed]
  • Robbins DC, Blix PM, Rubenstein AH, Kanazawa Y, Kosaka K, Tager HS. A human proinsulin variant at arginine 65. Nature. 1981 Jun 25;291(5817):679–681. [PubMed]
  • Robbins DC, Shoelson SE, Rubenstein AH, Tager HS. Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion. J Clin Invest. 1984 Mar;73(3):714–719. [PMC free article] [PubMed]
  • Shoelson S, Haneda M, Blix P, Nanjo A, Sanke T, Inouye K, Steiner D, Rubenstein A, Tager H. Three mutant insulins in man. Nature. 1983 Apr 7;302(5908):540–543. [PubMed]
  • Tager HS. Lilly lecture 1983. Abnormal products of the human insulin gene. Diabetes. 1984 Jul;33(7):693–699. [PubMed]
  • Kwok SC, Steiner DF, Rubenstein AH, Tager HS. Identification of a point mutation in the human insulin gene giving rise to a structurally abnormal insulin (insulin Chicago). Diabetes. 1983 Sep;32(9):872–875. [PubMed]
  • Haneda M, Chan SJ, Kwok SC, Rubenstein AH, Steiner DF. Studies on mutant human insulin genes: identification and sequence analysis of a gene encoding [SerB24]insulin. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6366–6370. [PubMed]
  • Bell GI, Karam JH, Rutter WJ. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Blattner FR, Blechl AE, Denniston-Thompson K, Faber HE, Richards JE, Slightom JL, Tucker PW, Smithies O. Cloning human fetal gamma globin and mouse alpha-type globin DNA: preparation and screening of shotgun collections. Science. 1978 Dec 22;202(4374):1279–1284. [PubMed]
  • Smithies O, Blechl AE, Denniston-Thompson K, Newell N, Richards JE, Slightom JL, Tucker PW, Blattner FR. Cloning human fetal gamma globin and mouse alpha-type globin DNA: characterization and partial sequencing. Science. 1978 Dec 22;202(4374):1284–1289. [PubMed]
  • Benton WD, Davis RW. Screening lambdagt recombinant clones by hybridization to single plaques in situ. Science. 1977 Apr 8;196(4286):180–182. [PubMed]
  • Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM. Sequence of the human insulin gene. Nature. 1980 Mar 6;284(5751):26–32. [PubMed]
  • Sanger F, Coulson AR, Barrell BG, Smith AJ, Roe BA. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. [PubMed]
  • Messing J, Crea R, Seeburg PH. A system for shotgun DNA sequencing. Nucleic Acids Res. 1981 Jan 24;9(2):309–321. [PMC free article] [PubMed]
  • Maxam AM, Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. [PubMed]
  • Ullrich A, Dull TJ, Gray A, Brosius J, Sures I. Genetic variation in the human insulin gene. Science. 1980 Aug 1;209(4456):612–615. [PubMed]
  • Yu SS, Kitbachi AE. Biological activity of proinsulin and related polypeptides in the fat tissue. J Biol Chem. 1973 Jun 10;248(11):3753–3761. [PubMed]
  • Kidd VJ, Wallace RB, Itakura K, Woo SL. alpha 1-antitrypsin deficiency detection by direct analysis of the mutation in the gene. Nature. 1983 Jul 21;304(5923):230–234. [PubMed]
  • Docherty K, Steiner DF. Post-translational proteolysis in polypeptide hormone biosynthesis. Annu Rev Physiol. 1982;44:625–638. [PubMed]
  • Docherty K, Carroll RJ, Steiner DF. Conversion of proinsulin to insulin: involvement of a 31,500 molecular weight thiol protease. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4613–4617. [PubMed]
  • Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature. 1983 Apr 21;302(5910):716–718. [PubMed]
  • Brennan SO, Carrell RW. A circulating variant of human proalbumin. Nature. 1978 Aug 31;274(5674):908–909. [PubMed]
  • Abdo Y, Rousseaux J, Dautrevaux M. Proalbumin Lille, a new variant of human serum albumin. FEBS Lett. 1981 Aug 31;131(2):286–288. [PubMed]

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