RNA Splicing Is Responsive to MBNL1 Dose 英文参考文献.docVIP

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RNA Splicing Is Responsive to MBNL1 Dose 英文参考文献.doc

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RNA Splicing Is Responsive to MBNL1 Dose 英文参考文献

RNASplicingIsResponsivetoMBNL1Dose SonaliP.Jog1,SharanPaul1¤,WaruneeDansithong1¤,StephanieTring1,LucioComai2*,SitaReddy1* 1DepartmentofBiochemistryandMolecularBiology,InstituteforGeneticMedicine,UniversityofSouthernCalifornia,LosAngeles,California,UnitedStatesofAmerica, 2DepartmentMolecularMicrobiologyandImmunology,InstituteforGeneticMedicine,UniversityofSouthernCalifornia,LosAngeles,California,UnitedStatesofAmerica Abstract Myotonicdystrophy(DM1)isahighlyvariable,multi-systemdisorderresultingfromtheexpansionofanuntranslatedCTG tractinDMPK.InDM1expandedCUGrepeatRNAsformhairpinsecondarystructuresthatbindandaberrantlysequesterthe RNAspliceregulator,MBNL1.RNAsplicedefectsresultingasaconsequenceofMBNL1depletionhavebeenshowntoplaya keyroleinthedevelopmentofDM1pathology.Inpatientpopulations,boththenumberandseverityofDM1symptoms increase broadly as a function of CTG tract length. However significant variability in the DM1 phenotype is observed in patientsencodingsimilarCTGrepeatnumbers.HerewedemonstratethatagradualdecreaseinMBNL1levelsresultsboth intheexpansionoftherepertoireofsplicedefectsandanincreaseintheseverityofthesplicealterations.Thus,MBNL1loss doesnothaveanallornoneoutcomebutrathershowsagradedeffectonthenumberandseverityoftheensuingsplice defects.Ourresultssuggestthatonceacriticalthresholdisreached,relativelysmalldosevariationsoffreeMBNL1levels, whichmayreflectmodestchangesinthesizeoftheCUGtractortheextentofhairpinsecondarystructureformation,can significantlyalterthenumberandseverityofspliceabnormalitiesandthuscontributetothephenotypevariabilityobserved inDM1patients. Citation: Jog SP, Paul S, Dansithong W, Tring S, Comai L, et al. (2012) RNA Splicing Is Responsive to MBNL1 Dose. PLoS ONE 7(11): e48825. doi:10.1371/ journal.pone.0048825 Editor:RalfKrahe,UniversityofTexasMDAndersonCancerCenter,UnitedStatesofAmerica ReceivedFebruary11,2011;AcceptedOctober3,2012;PublishedNovember15,2012 Copyright:?2012Jogetal.Thisisanopen-accessarticledistributedunderthetermsoftheC