title: Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.
abstract: The nucleotide sequence was determined for all 22 exons of the insulin receptor gene from three patients with genetic syndromes associated with extreme insulin resistance. In all three patients, insulin resistance was caused by decreased insulin binding to the cell surface. The patient with leprechaunism (leprechaun/Winnipeg) came from a consanguineous pedigree and was homozygous for a missense mutation substituting arginine for His209 in the alpha-subunit of the insulin receptor. The other two patients were both compound heterozygotes with a nonsense mutation in one allele of the insulin receptor gene, and a missense mutation in the other allele. In the patient with the Rabson-Mendenhall syndrome (patient RM-1), the missense mutation substituted lysine for Asn15 in the alpha-subunit. In the patient with type A extreme insulin resistance (patient A-1), the missense mutation substituted serine for Asn462 in the alpha-subunit. Both nonsense mutations markedly reduced the levels of insulin receptor mRNA transcribed from the alleles with the nonsense mutation as compared to the transcripts from the other allele. The reduction in the level of mRNA would be predicted to greatly reduce the rate at which the truncated receptors would be synthesized. Furthermore, the truncated receptors would be severely impaired in their ability to mediate insulin action.
authors.affiliation: Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
authors.forename: H
authors.initials: H
authors.lastname: Kadowaki
authors.forename: M M
authors.initials: MM
authors.lastname: Rechler
authors.forename: M
authors.initials: M
authors.lastname: Serrano-Rios
authors.forename: J
authors.initials: J
authors.lastname: Roth
authors.forename: P
authors.initials: P
authors.lastname: Gorden
authors.forename: S I
authors.initials: SI
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D015870:Gene Expression; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D009841:Oligonucleotides; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D015345:Oligonucleotide Probes; D009841:Oligonucleotides; D012333:RNA, Messenger; D011972:Receptor, Insulin