title: A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto).
abstract: 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.
authors.affiliation: Department of Metabolism and Clinical Nutrition, Kyoto University Faculty of Medicine, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yano
authors.forename: N
authors.initials: N
authors.lastname: Kitano
authors.forename: M
authors.initials: M
authors.lastname: Morimoto
authors.forename: K S
authors.initials: KS
authors.lastname: Polonsky
authors.forename: H
authors.initials: H
authors.lastname: Imura
authors.forename: Y
authors.initials: Y
authors.lastname: Seino
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D015139:Blotting, Southern; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004247:DNA; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics*; D007328:Insulin / Q000097:blood / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011384:Proinsulin / Q000097:blood / Q000235:genetics
chemical_list: D007328:Insulin; D004247:DNA; D011384:Proinsulin