Charcot-Marie-Tooth–Linked Mutant GARS Is Toxic to Peripheral Neurons Independent of Wild-Type GARS Levels 英文参考文献.docVIP

Charcot-Marie-Tooth–LinkedMutantGARSIsToxicto PeripheralNeuronsIndependentofWild-TypeGARS Levels WilliamW.Motley1,2,3,KevinL.Seburn1,MirHussainNawaz4,KathyE.Miers1,JunCheng5 ,Anthony Antonellis5,6,7,EricD.Green5,KevinTalbot3,8,Xiang-LeiYang4,KennethH.Fischbeck2,RobertW. Burgess1* 1TheJacksonLaboratory,BarHarbor,Maine,UnitedStatesofAmerica,2NeurogeneticsBranch,NationalInstituteofNeurologicalDisordersandStroke,NationalInstitutes ofHealth,Bethesda,Maryland,UnitedStatesofAmerica,3MRCFunctionalGenomicsUnit,UniversityofOxford,Oxford,UnitedKingdom,4TheScrippsResearchInstitute, LaJolla,California,UnitedStatesofAmerica,5GenomeTechnologyBranch,NationalHumanGenomeResearchInstitute,NationalInstitutesofHealth,Bethesda,Maryland, United States ofAmerica, 6Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 7Department of Neurology,UniversityofMichiganMedicalSchool,AnnArbor,Michigan,UnitedStatesofAmerica,8DepartmentofClinicalNeurology,UniversityofOxford,JohnRadcliffe Hospital,Oxford,UnitedKingdom Abstract Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutationsintheglycyl-tRNAsynthetasegene(GARS).InadditiontoGARS,mutationsinthreeothertRNAsynthetasegenes causesimilarneuropathies,althoughtheunderlyingmechanismsarenotfullyunderstood.Toaddressthis,wegenerated transgenic mice that ubiquitously over-express wild-type GARS and crossed them to two dominant mouse models of CMT2D to distinguish loss-of-function and gain-of-function mechanisms. Over-expression of wild-type GARS does not improve the neuropathy phenotype in heterozygous Gars mutant mice, as determined by histological, functional, and behavioraltests.TransgenicGARSisabletorescueapathologicalpointmutationasahomozygoteorincomplementation tests with a Gars null allele, demonstrating the functionality of the transgene and revealing a recessive loss-of-function component of the point mutation. Missense mut