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《Identification and Functional Characterization of CardiacTroponin I As a Novel Disease Gene in AutosomalDominant Dilated Cardiomyopathy心脏的识别与功能鉴定 肌钙蛋白I作为Autosomal新的疾病基因 显性扩张型心肌病》由会员上传分享，免费在线阅读，更多相关内容在学术论文-天天文库。
1、ClinicalResearchIdentificationandFunctionalCharacterizationofCardiacTroponinIAsaNovelDiseaseGeneinAutosomalDominantDilatedCardiomyopathySebastianCarballo,PaulRobinson,RobynOtway,DianeFatkin,JanD.H.Jongbloed,NicolaasdeJonge,EdwardBlair,J.PetervanTintelen,CharlesRedwood,HughWatkinsRati
2、onale:Idiopathicdilatedcardiomyopathy(DCM)isinheritedinapproximatelyonethirdofcases,usuallyasanautosomaldominanttrait.Morethan30locihavebeenidentified,severalofwhichencodesarcomericproteinswhichcanalsobemutatedtocausehypertrophiccardiomyopathy.Onecontractileproteingenewellknownasahyp
3、ertrophiccardiomyopathydiseasegene,butwithnoreportedmutationinautosomaldominantDCM,isTNNI3whichencodescardiactroponinI.Objective:TotestTNNI3asacandidategene,apanelof96probandswithDCMwasanalyzed.MethodsandResults:GenomicDNAwasisolatedandTNNI3exonsscreenedbyheteroduplexanalysis.Exonswi
4、thaberrantprofilesweresequencedandvariantsevaluatedbysegregationanalysisandstudyofnormalcontrols.Wereport2novelTNNI3missensemutations,Lys36GlnandAsn185Lys,eachassociatedwithsevereandearlyonsetfamilialDCM.Ofthe5mutationcarriers,cardiactransplantationwasrequiredin3,atages6,15,and242ye
5、ars.AnalysisofCaregulationofactin-tropomyosin–activatedmyosinATPasebytroponinrevealedthat2troponinreconstitutedwitheithermutanttroponinIgavelowermaximumATPaseratesandlowerCa2sensitivitythanwildtype.Furthermore,mutantthinfilamentshadreducedCaaffinitycomparedwithnormal.Conclusions:Th
6、efunctionalalterationsmirrorcloselyaconsistentphenotypefoundinprovenDCMmutationsinotherthinfilamentproteins,thussupportingtheinterpretationthatthesemutationsaredisease-causing.ThesearethefirstreportedautosomaldominantDCM-causingmutationsinTNNI3,andsothefindingsexpandthespectrumofdise
7、ase-causinggenesthatleadtoeitherhypertrophiccardiomyopathyorDCMdependingontheDownloadedfromhttp://ahajournals.orgbyonAugust12,2018specificmutation.(CircRes.2009;105:375-382.)2KeyWords:Caregulationcardiomyopathycontractilitydilatedcardiomyopathymutationilatedcardiomyopathy(DCM)ha
8、saprevalence
