title: Analysis of the insulin-like growth factor 1 receptor gene in children born small for gestational age: in vitro characterization of a novel mutation (p.Arg511Trp).
abstract: BACKGROUND
  Insulin-like growth factor 1 insensitivity caused by IGF1R mutations has been previously identified as one of the causes of growth impairment in children born small for gestational age (SGA).
  
  
  OBJECTIVE
  To analyse the IGF1R in children born SGA.
  
  
  METHODS
  From an initial cohort of 54 sequential children born SGA, without catch-up growth, 25 children were selected for this IGF1R study due to the presence of serum IGF-1 values above the mean for their age and sex.
  
  
  METHODS
  The proximal IGF1R promoter region, the entire coding region and the exon-intron boundaries were directly sequenced, and multiplex ligation-dependent probe amplification analysis was performed. Fibroblast cultures were developed from one patient with a mutation for the in vitro characterization of IGF-1 insensitivity.
  
  
  RESULTS
  The copy number variation analysis did not identify deletions involving the IGF1R gene. We identified two children carrying heterozygous nucleotide substitutions in IGF1R: c.16G>A/p.Gly6Arg and c.1531C>T/p.Arg511Trp. The first variant (p.Gly6Arg) was identified in control subjects (0·3%) and in a relative with normal growth; thus, it was considered to be a rare benign allelic variation. The second variant (p.Arg511Trp) was not found in 306 alleles from control subjects, and it segregated with the growth impairment phenotype in the patient's family. Fibroblasts obtained from this patient had a significantly reduced proliferative response and AKT phosphorylation after IGF-1 stimulation compared with control fibroblasts.
  
  
  CONCLUSIONS
  The identification of an inactivating IGF1R mutation in the present cohort should encourage further studies of larger series to establish the precise frequency of this molecular defect in children with growth impairment of a prenatal onset.
authors.affiliation: Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Leal
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Montenegro
authors.forename: Renata F
authors.initials: RF
authors.lastname: Saito
authors.forename: Tamaya C
authors.initials: TC
authors.lastname: Ribeiro
authors.forename: Debora C
authors.initials: DC
authors.lastname: Coutinho
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D020125:Mutation, Missense; D010375:Pedigree; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D014364:Tryptophan / Q000235:genetics
chemical_list: D014364:Tryptophan; D001120:Arginine; D017526:Receptor, IGF Type 1