STUDIES ON PATHOGENESIS OF WAARDENBURG SYNDROME TYPE ⅡAND TIETZ SYNDROME RESULTING FROM MITF GENE MUTATIONS-中国Betway体育网页登陆

摘要 Microphthalmia-associatedtranscriptionfactor(MITF)controlsmelanocytesurvivalanddifferentiationthroughdirectlyregulatingtheexpressionofthetyrosinase(TYR)andtyrosinase-relatedproteins1and2(TYRP1andTYRP2)genes.MITFmutationshavebeenreportedtoresultinanabnormalmelanocytedevel-opmentandleadtoWaardenburgsyndrometype2(WS2),characterizedbyvariabledegreesofsensorineu-ralhearinglossandpatchyregionaldistributionofhypopigmentation.Recently,MITFwasalsoindicatedasacausativegeneforamoreseveresyndrome,theTietzSyndrome(TS),characterizedbygeneralizedhy-popigmentationandcompletehearingloss.However,fewfunctionalstudieshavebeenperformedtocom-parethediseases-causingmutations.Here,weanalyzedtheinvitroactivityoftworecentidentifiedWS2-as-sociatedmutation(p.R217Iandp.T192fsX18)andoneTS-associatedmutationp.N210K.TheR217IMITFretainedpartialactivity,normalDNA-bindingabilityandnucleardistribution,whereastheT192fsX18MITFfailedtoactivateTYRpromoterduetolossofDNA-bindingactivity,andaberrantsubcellularlocalization.TheaberrantsubcellularlocalizationofT192fsX18MITFmaybecausedbydeletionofaputativenuclearlocalizationsignal(NLS)ataa213-218(ERRRRF).Indeed,MITFwithdeletionoftheNLSfragmentfailedtotranslocateintothenucleusandactivatedtheTYRpromoter.TaggingthisNLStoGFPpromotedthegreenfluorescenceprotein(GFP)translocatedintothenucleus.ThesurprisingfindingofourstudyisthataTS-as-sociatedMITFmutation,N210K,showedcomparableinvitroactivityasWT.Thus,thepossibleinvolve-mentofMITFinTSanditsunderlyingmechanismsstillneedfurtherinvestigation.

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STUDIES ON PATHOGENESIS OF WAARDENBURG SYNDROME TYPE ⅡAND TIETZ SYNDROME RESULTING FROM MITF GENE MUTATIONS

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