title: A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism.
abstract: We report a homozygous missense mutation at position 1092 (substitution of glutamine for arginine) in the tyrosine kinase domain of the insulin receptor in a patient with leprechaunism associated with severe insulin resistance and intrauterine growth retardation. Site-directed mutagenesis as well as analyses of the patient's lymphocytes revealed that this mutation causes a marked decrease in tyrosine kinase activity of the insulin receptor without any defect in insulin binding, which causes severe defects in insulin-stimulated glucose transport, glycogen synthesis and DNA synthesis. Thus, this is the first homozygous mutation resulting in a selective-kinase defect of the insulin receptor. Interestingly, the parents who are cousins and are heterozygous for the mutation have type A insulin resistance syndrome. This correlation between genotype and phenotype in a single pedigree suggests that the severity of the mutation will determine the phenotype. Based upon this assumption, we have been successful in prenatal diagnosis of the fifth child. Furthermore, we have demonstrated the effectiveness of clinical administration of insulin-like growth factor-I (IGF-I) in this patient and in vitro analysis of the patient's skin fibroblasts, suggesting that IGF-I can compensate for insulin action via the IGF-I receptor in a patient almost lacking functional insulin receptors.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Kadowaki
authors.forename: K
authors.initials: K
authors.lastname: Momomura
authors.forename: Y
authors.initials: Y
authors.lastname: Fukushima
authors.forename: T
authors.initials: T
authors.lastname: Orban
authors.forename: T
authors.initials: T
authors.lastname: Okai
authors.forename: Y
authors.initials: Y
authors.lastname: Taketani
authors.forename: Y
authors.initials: Y
authors.lastname: Akanuma
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000328:Adult; D000649:Amniocentesis; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts; D006006:Glycogen Synthase / Q000096:biosynthesis; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012867:Skin / Q000378:metabolism; D013577:Syndrome; D014162:Transfection
chemical_list: D007328:Insulin; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D004247:DNA; D006006:Glycogen Synthase; D011972:Receptor, Insulin