title: Identification of two novel insulin receptor mutations, Asp59Gly and Leu62Pro, in type A syndrome of extreme insulin resistance.
abstract: To elucidate genetic determinants of insulin resistance, we investigated insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) genes, in vitro IR function and in vivo insulin sensitivity in a family with Type A syndrome. Two missense IR mutations (Asp59Gly and Leu62Pro) found in the proband, resulted in reduction by 90% of insulin binding to erythrocytes, decreased receptor autophosphorylation and a dramatic reduction of insulin sensitivity. The proband and mother were heterozygote for Gly972Arg IRS-1 variant. Asp59Gly mutation, also carried by proband's brother with no consequence on insulin sensitivity, was inherited from the mother who is diabetic and insulin resistant and Leu62Pro was from the father. We conclude that severity of insulin resistance in the proband may be explained by the genetic condition of compound heterozygote for IR mutations while severe insulin resistance in the mother raises the possibility that other genetic factors, like IRS-1 polymorphisms, may contribute to the phenotypic expression of IR mutations.
authors.affiliation: Laboratoire d'Endocrinologie Moléculaire, Institut Universitaire de Recherche Clinique and Centre de Recherche de Biochimie Macromoléculaire, ERS 155 CNRS, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Rouard
authors.forename: F
authors.initials: F
authors.lastname: Macari
authors.forename: O
authors.initials: O
authors.lastname: Bouix
authors.forename: C
authors.initials: C
authors.lastname: Lautier
authors.forename: J F
authors.initials: JF
authors.lastname: Brun
authors.forename: P
authors.initials: P
authors.lastname: Lefebvre
authors.forename: E
authors.initials: E
authors.lastname: Renard
authors.forename: J
authors.initials: J
authors.lastname: Bringer
authors.forename: C
authors.initials: C
authors.lastname: Jaffiol
authors.forename: F
authors.initials: F
authors.lastname: Grigorescu
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D005260:Female; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007457:Iodine Radioisotopes; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007457:Iodine Radioisotopes; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin