Mutations in CHMP2B in Lower Motor Neuron Predominant Amyotrophic Lateral Sclerosis (ALS) 英文参考文献.docVIP

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Mutations in CHMP2B in Lower Motor Neuron Predominant Amyotrophic Lateral Sclerosis (ALS) 英文参考文献.doc

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Mutations in CHMP2B in Lower Motor Neuron Predominant Amyotrophic Lateral Sclerosis (ALS) 英文参考文献

MutationsinCHMP2BinLowerMotorNeuron PredominantAmyotrophicLateralSclerosis(ALS) LauraE.Cox1,LauraFerraiuolo1,EmilyF.Goodall1,PaulR.Heath1,AdrianHigginbottom1 ,Heather Mortiboys1,HannahC.Hollinger1,JudithA.Hartley1,AliceBrockington1,ChristineE.Burness1,KarenE. Morrison2,StephenB.Wharton1,AndrewJ.Grierson1,PaulG.Ince1,JanineKirby1.,PamelaJ.Shaw1*. 1DepartmentofNeuroscience,UniversityofSheffield,Sheffield,SouthYorkshire,UnitedKingdom,2DepartmentofNeurology,UniversityofBirmingham,Birmingham, EastMidlands,UnitedKingdom Abstract Background: Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporaldementia(FTD)in3–10%ofpatients.AmutationinCHMP2BwasrecentlyidentifiedinaDanishpedigree withautosomaldominantFTD.Subsequently,twounrelatedpatientswithfamilialALS,oneofwhomalsoshowedfeatures of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutationsinCHMP2BcontributemorebroadlytoALSpathogenesis. Methodology/PrincipalFindings:SequencingofCHMP2Bin433ALScasesfromtheNorthofEnglandidentified4cases carrying 3 missense mutations, including one novel mutation, p.Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistentwiththelowermotorneuronpredominant(progressivemuscularatrophy(PMA))variantofALS.Onlyonehada recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2Bcases,comparedtocontrols,showedadistinctgeneexpressionsignaturewithsignificantdifferentialexpression predictingdisassemblyofcellstructure;increasedcalciumconcentrationintheERlumen;decreaseintheavailabilityofATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repressionoftranslation.TransfectionofmutantCHMP2BintoHEK-293andCOS-7cellsresultedintheformationoflarge cyt