title: A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation.
abstract: BACKGROUND
  Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders.
  
  
  OBJECTIVE
  Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation.
  
  
  METHODS
  At birth, the girl's length was 47 cm [-1.82 sd score (SDS)], and her weight was 2250 g (-2.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS).
  
  
  RESULTS
  Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum.
  
  
  CONCLUSIONS
  The V599E-IGF1R mutation interferes with the receptor's trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient's wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.
authors.affiliation: University Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 20a, D-04103 Leipzig, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Wallborn
authors.forename: Stefan
authors.initials: S
authors.lastname: Wüller
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klammt
authors.forename: Tassilo
authors.initials: T
authors.lastname: Kruis
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kratzsch
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schmidt
authors.forename: Marina
authors.initials: M
authors.lastname: Schlicke
authors.forename: Eva
authors.initials: E
authors.lastname: Müller
authors.forename: Hildegard Schmitz
authors.initials: HS
authors.lastname: van de Leur
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.forename: Roland
authors.initials: R
authors.lastname: Pfäffle
mesh_terms: D019943:Amino Acid Substitution; D001724:Birth Weight; D049628:Body Size; D003072:Cognition Disorders / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D018698:Glutamic Acid / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics; D008831:Microcephaly / Q000235:genetics; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D014633:Valine / Q000235:genetics
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D018698:Glutamic Acid; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D014633:Valine