title: A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.
abstract: Insulin binds to a receptor on the cell surface, thereby triggering a biological response within the target cell. Mutations in the insulin receptor gene can render the cell resistant to the biological action of insulin. We have studied a family in which two sisters have a genetic form of insulin-resistant diabetes mellitus. The technique of homozygosity mapping has been used to demonstrate that the mutation causing diabetes in this consanguineous family is genetically linked to the insulin receptor gene. The two insulin-resistant sisters are homozygous for a mutation encoding substitution of valine for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. Transfection of mutant insulin receptor cDNA into NIH3T3 cells demonstrated that the Val382 mutation impaired post-translational processing and retarded transport of the insulin receptor to the plasma membrane. Thus, the mutation causes insulin resistance by decreasing the number of insulin receptors on the surface of the patients' cells.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: D
authors.initials: D
authors.lastname: Accili
authors.forename: C
authors.initials: C
authors.lastname: Frapier
authors.forename: L
authors.initials: L
authors.lastname: Mosthaf
authors.forename: C
authors.initials: C
authors.lastname: McKeon
authors.forename: S C
authors.initials: SC
authors.lastname: Elbein
authors.forename: M A
authors.initials: MA
authors.lastname: Permutt
authors.forename: E
authors.initials: E
authors.lastname: Ramos
authors.forename: E
authors.initials: E
authors.lastname: Lander
authors.forename: A
authors.initials: A
authors.lastname: Ullrich
authors.forename: S I
authors.initials: SI
authors.lastname: Taylor
mesh_terms: D002478:Cells, Cultured; D003001:Cloning, Molecular; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011499:Protein Processing, Post-Translational; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014633:Valine
chemical_list: D011972:Receptor, Insulin; D014633:Valine