title: A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization.
abstract: BACKGROUND
  IGF-I/IGF-I receptor (IGF-IR) signaling pathways play important roles in longitudinal growth. A novel Arg481Glu (R481Q) mutation in IGF-IR was detected in a family with intrauterine and postnatal growth retardation.
  
  
  OBJECTIVE
  The objective of the study was to explore the mechanism whereby the R481Q mutation may be causative in growth retardation.
  
  
  METHODS
  A 13-yr-old girl with short stature was studied for functional analysis of the R481Q mutation in the IGF-IR.
  
  
  RESULTS
  Two members of a family who showed intrauterine and postnatal growth retardation, with increased serum IGF-I levels, demonstrated a substitution of arginine for glutamine at 481 (R481Q) in the IGF-IR. This mutation results in the formation of an altered fibronectin type III domain within the alpha-subunit. NIH-3T3 fibroblasts that overexpress the human wild-type or R481Q mutant IGF-IR demonstrated normal cell surface ligand binding by 125I-IGF-I binding assay. However, the fold increase of IGF-I stimulated tyrosine phosphorylation of the IGF-IR beta-subunit as well as downstream activation of ERK1/2 and Akt was reduced in cells overexpressing the mutant receptor. Additionally, basal and IGF-I-stimulated levels of cell proliferation were also reduced in cells overexpressing the mutant receptor.
  
  
  CONCLUSIONS
  Our results demonstrate that NIH-3T3 cells overexpressing a mutant form of the Igf1r gene, in which arginine at 481 is substituted by glutamine, lead to reduced levels of the fold increase of IGF-IR beta-subunit phosphorylation as well as ERK1/2 and Akt phosphorylation and was accompanied by decreased cell proliferation. These results are postulated to be the cause of intrauterine and postnatal growth retardation in the described patients.
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, The Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Inagaki
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tiulpakov
authors.forename: Petr
authors.initials: P
authors.lastname: Rubtsov
authors.forename: Polina
authors.initials: P
authors.lastname: Sverdlova
authors.forename: Valentina
authors.initials: V
authors.lastname: Peterkova
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.forename: Sergei
authors.initials: S
authors.lastname: Terekhov
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
mesh_terms: D016475:3T3 Cells; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D001827:Body Height / Q000235:genetics*; D002648:Child; D003001:Cloning, Molecular; D005260:Female; D005973:Glutamine; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D017526:Receptor, IGF Type 1 / Q000235:genetics*
chemical_list: D005973:Glutamine; D007334:Insulin-Like Growth Factor I; D001120:Arginine; D017526:Receptor, IGF Type 1