RNAsplicinganddisease:animalmodelstotherapiesMatíasMontes1,2,BrianneL.Sanford2,DanielF.Comiskey1,2,andDawnS.Chandler1,2,3,*1Molecular,CellularandDevelopmentalBiologyGraduateProgramandTheCenterforRNABiology,TheOhioStateUniversity,Columbus,Ohio2CenterforChildhoodCancerandBloodDiseases,TheResearchInstituteatNationwideChildren’sHospital,Columbus,Ohio3DepartmentofPediatrics,TheOhioStateUniversityCollegeofMedicine,Columbus,OhioAbstractAlternativesplicingofpre-messengerRNAincreasesgeneticdiversityandrecentstudiesestimatethatmosthumanmulti-exongenesarealternativelyspliced.Ifthisprocessisnothighlyregulatedandaccurate,itleadstomis-splicingeventswhichmayresultinproteinswithalteredfunction.Agrowingbodyofworkhasimplicatedmis-splicingeventsascontributingtoawiderangeofdiseasesincludingcancer,neurodegenerativediseases,andmusculardystrophies.Understandingthemechanismsthatcauseaberrantsplicingeventsandhowthisleadstodiseaseisvitalfordesigningeffectivetherapeuticstrategies.Thisreviewfocusesonadvancesintherapiestargetingsplicingandhighlightstheanimalmodelsdevelopedtorecapitulatediseasephenotypesasamodelfortestingthesetherapies.KeywordsRNAsplicing;disease;animalmodelsDisruptedsplicingindiseaseOurknowledgeaboutpre-mRNAmaturationhasgreatlyexpandedsincethediscoveryof“split”genesbyRichardRobertsandPhillipSharpin1977,forwhichtheywerejointlyawardedtheNobelPrizein1993fortheirindependentdiscoveries[1,2].Wenowknowthateukaryoticgenescontainaseriesofexonsandintrons,thelatterofwhichhavetoberemovedduringRNAmaturationinorderforthematuremRNAtobetranslatedintoprotein(Box1).Splicingisapreciseprocessbynecessityasmistakesinsplicingcanalsoleadtounintendedeffectscausingcodingorframeshiftmutations.Inordertodirectsplicingeffectivelywithhighfidelity,theprocessreliesonsignalswithinthetranscriptitself,suchthesplicesitesandassociatedsequences,aswellasfactorsthatrecognizethemtofacilitate*Correspondence:chandler.135@osu.edu(D.S.Chandler).Publisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacc...
