title: Mutations in the NSD1 gene in patients with Sotos syndrome associate with endocrine and paracrine alterations in the IGF system.
abstract: OBJECTIVE
  To investigate the effect of nuclear receptor Su-var, 3-9, enhancer of zeste, trithorax (SET) domain-containing protein 1 (NSD1) gene alteration in patients with Sotos syndrome on plasma IGFs and IGF-binding proteins (IGFBPs), as well as on the IGF/IGFBP system activity at the tissue level.
  
  
  METHODS
  Twenty-nine patients suspected of Sotos syndrome were divided into two groups: patients with heterozygous deletions or mutations in the NSD1 gene (NSD1(+/-)) (n=11) and subjects without (NSD1(+/+)) (n=18). Plasma samples (n=29) and skin fibroblasts (n=23) were obtained. The results of both groups were compared and related to reference values.
  
  
  METHODS
  IGF-I, IGF-II, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6 levels were determined by RIAs. The mitogenic response of fibroblasts to IGFs was investigated by [methyl-(3)H]thymidine incorporation. IGFBP-3 levels in the culture media were measured by RIA. IGFBP-3 mRNA expression was determined by real time RT-PCR.
  
  
  RESULTS
  NSD1(+/-) patients showed significantly altered levels of IGF-I (mean-1.2 SDS), IGF-II (-1.2), IGFBP-3 (-1.7), IGFBP-4 (-0.4), IGFBP-2 (+0.8) and IGFBP-6 (+1.5). The NSD1(+/+) patients did not differ from the reference, with the exception of the mean IGFBP-3 level (-1.3). Basal proliferation and mitogenic response to IGFs was diminished in NSD1(+/-) fibroblasts compared with NSD1(+/+) (basal, P=0.02; IGF-I, P<0.001; IGF-II, P=0.02). Compared with control fibroblasts, only the mitogenic response was diminished (basal, P=0.07; IGF-I, P=0.04; IGF-II, P=0.04). A trend of higher IGFBP-3 secretion after IGF-I stimulation (P=0.09) and 3.5-5 times higher mRNA expression of IGFBP-3 in basal conditions was found in NSD1(+/-) fibroblasts in comparison to controls.
  
  
  CONCLUSIONS
  NSD1(+/-) patients show endocrine and paracrine changes in the IGF system. These changes may contribute to the abnormal growth pattern.
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: De Boer
authors.forename: H A
authors.initials: HA
authors.lastname: Van Duyvenvoorde
authors.forename: E C
authors.initials: EC
authors.lastname: Willemstein-Van Hove
authors.forename: C M
authors.initials: CM
authors.lastname: Hoogerbrugge
authors.forename: J
authors.initials: J
authors.lastname: Van Doorn
authors.forename: J A
authors.initials: JA
authors.lastname: Maassen
authors.forename: M
authors.initials: M
authors.lastname: Karperien
authors.forename: J M
authors.initials: JM
authors.lastname: Wit
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004700:Endocrine System Diseases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood / Q000235:genetics; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000097:blood / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000166:cytology
chemical_list: D002352:Carrier Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D018976:Insulin-Like Growth Factor Binding Protein 6; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human