A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto)

J Clin Invest. 1992 Jun;89(6):1902-7. doi: 10.1172/JCI115795.


We have identified a 65-yr-old nonobese Japanese man with diabetes mellitus, fasting hyperinsulinemia (150-300 pM), and a reduced fasting C-peptide/insulin molar ratio of 2.5-3.0. Fasting hyperinsulinemia was also found in his son and daughter. Analysis of insulin isolated from the serum of the proband and his son by reverse-phase high performance liquid chromatography revealed a minor peak coeluting with human insulin and a major peak of proinsulin-like materials. The insulin gene of the patient was amplified by the polymerase chain reaction and the products were sequenced. A novel point mutation was identified in which guanine was replaced by thymine. The substitution gives rise to a new HindIII recognition site and results in the amino acid replacement of leucine for arginine at position 65. These results indicate that the amino-acid replacement prevents recognition of the C-peptide-A chain dibasic protease and results in an elevation of proinsulin-like materials in the circulation. Furthermore, in this family the proinsulin-like materials is due to a biosynthetic defect, inherited as an autosomal dominant trait. Rapid detection of this mutation can be accomplished by HindIII restriction enzyme mapping of polymerase chain reaction-generated DNA, which enables us to facilitate the diagnosis and screening.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Base Sequence
  • Blotting, Southern
  • Chromatography, Gel
  • Chromatography, High Pressure Liquid
  • DNA
  • Female
  • Humans
  • Hyperinsulinism / blood
  • Hyperinsulinism / genetics*
  • Insulin / blood
  • Insulin / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Polymerase Chain Reaction
  • Proinsulin / blood
  • Proinsulin / genetics


  • Insulin
  • DNA
  • Proinsulin