An Overgrowth Disorder Associated with Excessive Production of cGMP Due to a Gain-of-Function Mutation of the Natriuretic Peptide Receptor 2 Gene 英文参考文献.docVIP

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An Overgrowth Disorder Associated with Excessive Production of cGMP Due to a Gain-of-Function Mutation of the Natriuretic Peptide Receptor 2 Gene 英文参考文献.doc

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An Overgrowth Disorder Associated with Excessive Production of cGMP Due to a Gain-of-Function Mutation of the Natriuretic Peptide Receptor 2 Gene 英文参考文献

AnOvergrowthDisorderAssociatedwithExcessive ProductionofcGMPDuetoaGain-of-FunctionMutation oftheNatriureticPeptideReceptor2Gene KohjiMiura1,NoriyukiNamba1,MakotoFujiwara1,YasuhisaOhata1,HidekazuIshida1,TaichiKitaoka1, TakuoKubota1,HaruhikoHirai1,ChikahisaHiguchi2,NoriyukiTsumaki3,HidekiYoshikawa2, NorioSakai1,ToshimiMichigami4,KeiichiOzono1* 1Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan, 2Department of Orthopedics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan, 3Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Kyoto, Japan, 4DepartmentofBoneandMineralResearch,OsakaMedicalCenterandResearchInstituteforMaternalandChildHealth,Izumi,Osaka,Japan Abstract Wedescribeathree-generationfamilywithtallstature,scoliosisandmacrodactylyofthegreattoesandaheterozygous p.Val883Met mutation in Npr2, the gene that encodes the CNP receptor NPR2 (natriuretic peptide receptor 2). When expressedinHEK293Acells,themutantNpr2cDNAgeneratedintracellularcGMP(cyclicguanosinemonophosphate)inthe absenceofCNPligand.InthepresenceofCNP,cGMPproductionwasgreaterincellsthathadbeentransfectedwiththe mutantNpr2cDNAcomparedtowild-typecDNA.TransgenicmiceinwhichthemutantNpr2wasexpressedinchondrocytes drivenbythepromoterandintronicenhanceroftheCol11a2geneexhibitedanenhancedproductionofcGMPincartilage, leadingtoasimilarphenotypetothatobservedinthepatients.Inaddition,bloodcGMPconcentrationswereelevatedin thepatients.Theseresultsindicatethatp.Val883Metisaconstitutiveactivegain-of-functionmutationandelevatedlevelsof cGMPingrowthplatesleadtotheelongationoflongbones.OurfindingsrevealacriticalroleforNPR2inskeletalgrowthin bothhumansandmice,andmayprovideapotentialtargetforpreventionandtreatmentofdiseasescausedbyimpaired productionofcGMP. Citation:MiuraK,NambaN,FujiwaraM,OhataY,IshidaH,etal.(2012)AnOvergrowthDisorderAssociatedwithExcessiveProductionofcGMPDuetoaGain-of- FunctionMutatio