Diabetes Insipidus in Mice with a Mutation in Aquaporin-2 英文参考文献.docVIP

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Diabetes Insipidus in Mice with a Mutation in Aquaporin-2 英文参考文献.doc

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Diabetes Insipidus in Mice with a Mutation in Aquaporin-2 英文参考文献

DiabetesInsipidusinMicewithaMutation inAquaporin-2 David J.Lloyd1,Frank Wesley Hall2,Lisa M. Tarantino1,Nicholas Gekakis1* 1GenomicsInstituteoftheNovartisResearchFoundation,LaJolla,California,UnitedStatesofAmerica,2DepartmentofPathology,ScrippsClinic,LaJolla,California,United StatesofAmerica Congenitalnephrogenicdiabetesinsipidus(NDI)isadiseasecharacterizedbyfailureofthekidneytoconcentrateurine inresponsetovasopressin.Humankindredswithnephrogenicdiabetesinsipidushavebeenfoundtoharbormutations in the vasopressin receptor 2 (Avpr2) gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2) gene. Developmentofatreatmentisrendereddifficultduetothelackofaviableanimalmodel.Throughforwardgenetic screeningofethylnitrosourea-mutagenizedmice,wereporttheidentificationandcharacterizationofamousemodel ofNDI,withanF204VmutationintheAqp2gene.UnlikepreviouslyattemptedmurinemodelsofNDI,ourmicesurvive toadulthoodandmoreexactlyrecapitulatethehumandisorder.Previousinvitroexperimentsusingrenalcelllines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we havedirectlyproventhishypothesisofimproperAQP2translocationasthemoleculardefectinnephrogenicdiabetes insipidusintheintactorganism.Additionally,usingarenalcelllineweshowthatthemutatedprotein,AQP2-F204V,is retainedintheendoplasmicreticulumandthatthisabnormallocalizationcanberescuedbywild-typeprotein.This novelmousemodelallowsforfurthermechanisticstudiesaswellastestingofpharmacologicalandgenetherapiesfor NDI. Citation:LloydDJ,HallFW,TarantinoLM,GekakisN(2005)Diabetesinsipidusinmicewithamutationinaquaporin-2.PLoSGenet1(2):e20. resulting in severe NDI in humans [3,10]. Recessive Aqp2 mutations are generally thought to produce an abnormally Introduction Nephrogenic diabetes insipidus (NDI) is a disease charac- terized by excessive urination and thirst, despite normal productionoftheantidiuretichormoneargininevasopressin (AVP) [1]. The inherited forms are either X-linked