title: IGF-I sensitivity in Silver-Russell syndrome with IGF2/H19 hypomethylation.
abstract: BACKGROUND
  Silver-Russell syndrome (SRS) is characterized by intrauterine and postnatal growth retardation, typical facial appearance and body asymmetry. The mechanism of growth retardation is unclear. 50% of the patients have a paternal chromosome 11 epimutation-DNA hypomethylation of the imprinting center region 1 (ICR1) of the insulin-like growth factor 2 (IGF2)/H19 locus. SRS children who carry such an epimutation have increased levels of IGF-I and IGFBP-3 in relation to their stature and body weight, suggesting IGF-I resistance. No IGF-I receptor (IGF-1R) defect has been discovered. Therefore, another mechanism, probably an IGF-I post-receptor signaling defect, might be present.
  
  
  OBJECTIVE
  The aim of this in-vitro study was to examine: 1) if IGF-I- and IGF-II-induced fibroblast growth is different in SRS children with IGF2/H19 hypomethylation compared to controls; and 2) whether there is IGF-I insensitivity in this subgroup of SRS children due to IGF-I post-receptor signaling defects.
  
  
  METHODS
  Four SRS patients (two males, two females; 9.2 to 16.6 years of age) with an IGF2/H19 hypomethylation defect and three age-matched healthy controls were included in the in-vitro study. Cultivated skin fibroblasts from the patients and the healthy controls were used for the experiments. Proliferation rates of fibroblasts were measured in the presence or absence of recombinant human IGF-I and IGF-II using the commercially available 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test. PI3K (phosphoinositide 3-kinase) assay and NF-κB transcription factor assay were performed using ELISA in order to estimate the IGF-I-stimulated Akt phosphorylation and IκB phosphorylation, respectively.
  
  
  RESULTS
  Fibroblasts from SRS patients and fibroblasts from control individuals showed a comparable potential to proliferate in serum-free medium when stimulated with IGFs. No significant differences were found between both groups concerning Akt phosphorylation and IκB phosphorylation rates.
  
  
  CONCLUSIONS
  The results of the in-vitro study do not support the hypothesis that IGF-I/IGF-II resistance is a major pathogenetic mechanism responsible for the growth failure in the subgroup of SRS children with IGF2/H19 hypomethylation.
authors: University Children's Hospital, Pediatric Endocrinology and Diabetology, Hoppe-Seyler-Str. 1, D-72076 Tuebingen, Germany.
authors: D I
authors: DI
authors: Iliev
authors: University Children's Hospital, Pediatric Endocrinology and Diabetology, Hoppe-Seyler-Str. 1, D-72076 Tuebingen, Germany.
authors: K
authors: K
authors: Kannenberg
authors: University Children's Hospital, Pediatric Endocrinology and Diabetology, Hoppe-Seyler-Str. 1, D-72076 Tuebingen, Germany.
authors: K
authors: K
authors: Weber
authors: University Children's Hospital, Pediatric Endocrinology and Diabetology, Hoppe-Seyler-Str. 1, D-72076 Tuebingen, Germany. Electronic address: Gerhard.Binder@med.uni-tuebingen.de.
authors: G
authors: G
authors: Binder
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D019175:DNA Methylation / Q000187:drug effects; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008297:Male; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D056730:Silver-Russell Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D062085:RNA, Long Noncoding; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II
keywords: IGF-1R signal transduction; IGF2/H19 hypomethylation; Silver–Russell syndrome