Sotos Syndrome Is Associated with Deregulation of the MAPKERK-Signaling Pathway 英文参考文献.docVIP

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Sotos Syndrome Is Associated with Deregulation of the MAPKERK-Signaling Pathway 英文参考文献.doc

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Sotos Syndrome Is Associated with Deregulation of the MAPKERK-Signaling Pathway 英文参考文献

SotosSyndromeIsAssociatedwithDeregulationofthe MAPK/ERK-SignalingPathway RemcoVisser1*,EllieB.M.Landman2,JelleGoeman3,JanM.Wit1,MarcelKarperien2 1DepartmentofPediatrics,LeidenUniversityMedicalCenter,Leiden,TheNetherlands,2DepartmentofDevelopmentalBioEngineering,MIRAInstituteforBiomedical TechnologyandTechnicalMedicine,Enschede,TheNetherlands,3DepartmentofMedicalStatisticsandBioinformatics,LeidenUniversity,MedicalCenter,Leiden,The Netherlands Abstract Sotossyndrome(SoS)ischaracterizedbytallstature,characteristiccraniofacialfeaturesandmentalretardation.Itiscaused byhaploinsufficiencyoftheNSD1gene.Inthisstudy,ourobjectivewastoidentifydownstreameffectorsofNSD1andto maptheseeffectorsinsignalingpathwaysassociatedwithgrowth.Genome-wideexpressionstudieswereperformedon dermalfibroblastsfromSoSpatientswithaconfirmedNSD1abnormality.Tosubstantiatethoseresults,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 contributedstronglytothedifferentialexpressioninthispathway.Inaddition,adiminishedactivitystateoftheMAPK/ERK pathwaywasdemonstratedinSoS.TheRasInteractingProtein1(RASIP1)wasidentifiedtoexhibitupregulatedexpression 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 growthplates.Inshortstaturesyndromes suchashypochondroplasia andNoonansyndrome, theactivationlevelofthe FGF-MAPK/ERK-pathway in epiphyseal growthplates is adetermining factor forstaturalgrowth. Inanalogy,wepropose that deregulation of the MAPK/ERK pathway in SoS results in altered hypertrophic differentiation of NSD1 expressing chondroc