title: Sotos syndrome is associated with deregulation of the MAPK/ERK-signaling pathway.
abstract: Sotos syndrome (SoS) is characterized by tall stature, characteristic craniofacial features and mental retardation. It is caused by haploinsufficiency of the NSD1 gene. In this study, our objective was to identify downstream effectors of NSD1 and to map these effectors in signaling pathways associated with growth. Genome-wide expression studies were performed on dermal fibroblasts from SoS patients with a confirmed NSD1 abnormality. To substantiate those results, phosphorylation, siRNA and transfection experiments were performed. A significant association was demonstrated with the Mitogen-Activated Protein Kinase (MAPK) pathway. Members of the fibroblast growth factor family such as FGF4 and FGF13 contributed strongly to the differential expression in this pathway. In addition, a diminished activity state of the MAPK/ERK pathway was demonstrated in SoS. The Ras Interacting Protein 1 (RASIP1) was identified to exhibit upregulated expression in SoS. It was shown that RASIP1 dose-dependently potentiated bFGF induced expression of the MAPK responsive SBE reporter providing further support for a link between NSD1 and the MAPK/ERK signaling pathway. Additionally, we demonstrated NSD1 expression in the terminally differentiated hypertrophic chondrocytes of normal human epiphyseal growth plates. In short stature syndromes such as hypochondroplasia and Noonan syndrome, the activation level of the FGF-MAPK/ERK-pathway in epiphyseal growth plates is a determining factor for statural growth. In analogy, we propose that deregulation of the MAPK/ERK pathway in SoS results in altered hypertrophic differentiation of NSD1 expressing chondrocytes and may be a determining factor in statural overgrowth and accelerated skeletal maturation in SoS.
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands. r.visser@lumc.nl
authors.forename: Remco
authors.initials: R
authors.lastname: Visser
authors.forename: Ellie B M
authors.initials: EB
authors.lastname: Landman
authors.forename: Jelle
authors.initials: J
authors.lastname: Goeman
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation; D012867:Skin / Q000378:metabolism; D058495:Sotos Syndrome / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D047908:Intracellular Signaling Peptides and Proteins; C487329:RASIP1 protein, human; D016222:Fibroblast Growth Factor 2; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors