title: Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson-Mendenhall syndrome.
abstract: Homozygous or compound heterozygous mutations within the insulin binding domain of the human insulin receptor (INSR) are usually associated with severe impairment of insulin binding leading to Donohue syndrome ("Leprechaunism"), which is characterized by excessive hyperglycemia with hyperinsulinism, pre- and postnatal growth retardation, distinct dysmorphism and early death. Missense mutations in the beta subunits are commonly associated with a milder impairment of insulin binding and milder phenotype with prolonged survival and less dysmorphism, the so called Rabson-Mendenhall syndrome. We report on a 13-year-old girl with Donohue syndrome like dysmorphism, hyperinsulinism and prolonged survival due to two novel INSR missense mutations within the insulin binding domain. Unexpectedly, insulin binding assays and investigations of activation of central insulin signaling pathways in fibroblasts revealed no significant alterations. Instead, immunofluorescence studies showed abnormal perinuclear distribution of the INSR alpha and beta subunits. Our data indicate that the quality of insulin binding activity is correlated with survival, not with the dysmorphic phenotype, and it is not always a valid parameter for predicting INSR mutations as proposed.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 10, D-91054 Erlangen, Germany. Christian.Thiel@humgenet.uni-erlangen.de
authors.forename: Christian T
authors.initials: CT
authors.lastname: Thiel
authors.forename: Birgit
authors.initials: B
authors.lastname: Knebel
authors.forename: Ina
authors.initials: I
authors.lastname: Knerr
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: D
authors.initials: D
authors.lastname: Müller-Wieland
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Andre
authors.initials: A
authors.lastname: Reis
authors.forename: Helmuth-Günther
authors.initials: HG
authors.lastname: Dörr
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000150:complications / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006130:Growth Disorders / Q000150:complications / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome
chemical_list: D015703:Antigens, CD; D007328:Insulin; D021122:Protein Subunits; C435941:INSR protein, human; D011972:Receptor, Insulin