title: Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing.
abstract: A point mutation in the human insulin receptor gene in a patient with type A insulin resistance alters the amino acid sequence within the tetrabasic processing site of the proreceptor molecule from Arg-Lys-Arg-Arg to Arg-Lys-Arg-Ser. Epstein-Barr virus-transformed lymphocytes from this patient synthesize an insulin receptor precursor that is normally glycosylated and inserted into the plasma membrane but is not cleaved to mature alpha and beta subunits. Insulin binding to these cells is severely reduced but can be increased about fivefold by gentle treatment with trypsin, accompanied by the appearance of normal alpha subunits. These results indicate that proteolysis of the proreceptor is necessary for its normal full insulin-binding sensitivity and signal-transducing activity and that a cellular protease that is more stringent in its specificity than trypsin is required to process the receptor precursor.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, IL 60637.
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshimasa
authors.forename: S
authors.initials: S
authors.lastname: Seino
authors.forename: J
authors.initials: J
authors.lastname: Whittaker
authors.forename: T
authors.initials: T
authors.lastname: Kakehi
authors.forename: A
authors.initials: A
authors.lastname: Kosaki
authors.forename: H
authors.initials: H
authors.lastname: Kuzuya
authors.forename: H
authors.initials: H
authors.lastname: Imura
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
authors.forename: D F
authors.initials: DF
authors.lastname: Steiner
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D007328:Insulin; D011498:Protein Precursors; D012333:RNA, Messenger; C051512:insulin proreceptor; D004247:DNA; D011972:Receptor, Insulin; D014357:Trypsin