title: Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance.
abstract: We analyzed the insulin receptor gene in four patients with leprechaunism and one with type A insulin resistance. We detected novel and previously reported mutations. The novel mutants were expressed in Chinese hamster ovary cells to evaluate the consequences for insulin receptor function. A type A insulin resistance patient from Morocco was homozygous for Arg252His mutation, similar to a previously described type A patient from Japan. A patient with leprechaunism was homozygous for the Ser323Leu mutation, previously identified in homozygous form in two patients with Rabson-Mendenhall syndrome. Phenotypic expression of this mutation is variable. A patient with leprechaunism is compound heterozygous for the previously described Arg1092Trp mutation and a nonsense mutation in codon 897. Another patient with leprechaunism was homozygous for a novel Asn431Asp mutation, which only partially reduces insulin proreceptor processing and activation of signaling cascades. The novel Leu93Gln mutation that fully disrupts proreceptor processing was found in one allele in a patient with leprechaunism. A nonsense mutation at codon 1122 was in the other allele. These results expand the number of pathogenic insulin receptor mutations and demonstrate the variability in their phenotypic expression. The biochemical analysis of mutant insulin receptors does not reliably predict whether the phenotype will be leprechaunism, the Rabson-Mendenhall syndrome, or type A insulin resistance. The previously reported correlation between fibroblast insulin binding and duration of patient survival was not observed.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Centre, 2333 AL Leiden, The Netherlands. j.a.maassen@lumc.edu
authors.forename: J Antonie
authors.initials: JA
authors.lastname: Maassen
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tobias
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserilli
authors.forename: Turgut
authors.initials: T
authors.lastname: Tukel
authors.forename: Memnune
authors.initials: M
authors.lastname: Yuksel-Apak
authors.forename: Esther
authors.initials: E
authors.lastname: D'Haens
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: Francoise
authors.initials: F
authors.lastname: Féry
authors.forename: Gerard C M
authors.initials: GC
authors.lastname: van der Zon
mesh_terms: D000293:Adolescent; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics / Q000502:physiology; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007223:Infant; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D019000:Phosphotyrosine / Q000378:metabolism; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D007004:Hypoglycemic Agents; D007328:Insulin; D019000:Phosphotyrosine; D004247:DNA; D011972:Receptor, Insulin