Cdon Mutation and Fetal Ethanol Exposure Synergize to Produce Midline Signaling Defects and Holoprosencephaly Spectrum Disorders in Mice 英文参考文献.docVIP

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Cdon Mutation and Fetal Ethanol Exposure Synergize to Produce Midline Signaling Defects and Holoprosencephaly Spectrum Disorders in Mice 英文参考文献.doc

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Cdon Mutation and Fetal Ethanol Exposure Synergize to Produce Midline Signaling Defects and Holoprosencephaly Spectrum Disorders in Mice 英文参考文献

CdonMutationandFetalEthanolExposureSynergizeto ProduceMidlineSignalingDefectsand HoloprosencephalySpectrumDisordersinMice MingiHong,RobertS.Krauss* DepartmentofDevelopmentalandRegenerativeBiology,MountSinaiSchoolofMedicine,NewYork,NewYork,UnitedStatesofAmerica Abstract Holoprosencephaly(HPE)isaremarkablycommoncongenitalanomalycharacterizedbyfailuretodefinethemidlineofthe forebrainandmidface.HPEisassociatedwithheterozygousmutationsinSonichedgehog(SHH)pathwaycomponents,but clinical presentation is extremely variable and many mutation carriers are unaffected. It has been proposed that these observationsarebestexplainedbyamultiple-hitmodel,inwhichthepenetranceandexpressivityofanHPEmutationis enhanced by a second mutation or the presence of cooperating, but otherwise silent, modifier genes. Non-genetic risk factors are also implicated in HPE, and gene–environment interactions may provide an alternative multiple-hit model to purelygeneticmultiple-hitmodels;however,thereislittleevidenceforthiscontention.Wereporthereamousemodelin whichthereisdramaticsynergybetweenmutationofabonafideHPEgene(Cdon,whichencodesaSHHco-receptor)anda suspectedHPEteratogen,ethanol.LossofCdonandinuteroethanolexposurein129S6micegivelittleornophenotype individually, but together produce defects in early midline patterning, inhibition of SHH signaling in the developing forebrain,andabroadspectrumofHPEphenotypes.OurfindingsarguethatethanolisindeedariskfactorforHPE,but genetically predisposed individuals, such as those with SHH pathway mutations, may be particularly susceptible. Furthermore,gene–environmentinteractionsarelikelytobeimportantinthemultifactorialetiologyofHPE. Citation:HongM,KraussRS(2012)CdonMutationandFetalEthanolExposureSynergizetoProduceMidlineSignalingDefectsandHoloprosencephalySpectrum DisordersinMice.PLoSGenet8(10):e1002999.doi:10.1371/journal.pgen.1002999 Editor:JeanM.He′bert,AlbertEinsteinCollegeofMedicine,UnitedStatesofAmerica ReceivedNovember14,2011;AcceptedAugust14,2012;Published