Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J 英文参考文献.docVIP

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Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J 英文参考文献.doc

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Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J 英文参考文献

PathogenicMechanismoftheFIG4Mutation ResponsibleforCharcot-Marie-ToothDiseaseCMT4J GuyM.Lenk1,ColeJ.Ferguson1,ClementY.Chow1.¤,NatsukoJin2.,JulieM.Jones1,AdrienneE.Grant1, SergeyN.Zolov2,JesseJ.Winters3,RomanJ.Giger3,4,JamesJ.Dowling4,LoisS.Weisman2,3,MiriamH. Meisler1* 1DepartmentofHumanGenetics,UniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica,2LifeSciencesInstitute,UniversityofMichigan,AnnArbor, Michigan, United States of America, 3Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America, 4DepartmentofNeurology,UniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica Abstract CMT4JisasevereformofCharcot-Marie-ToothneuropathycausedbymutationofthephosphoinositidephosphataseFIG4/ SAC3.AffectedindividualsarecompoundheterozygotescarryingthemissensealleleFIG4-I41Tincombinationwithanull allele.Analysisusingtheyeasttwo-hybridsystemdemonstratedthattheI41TmutationimpairsinteractionofFIG4withthe scaffoldproteinVAC14.ThecriticalroleofthisinteractionwasconfirmedbythedemonstrationoflossofFIG4proteinin VAC14 null mice. We developed a mouse model of CMT4J by expressing a Fig4-I41T cDNA transgene on the Fig4 null background.Expressionofthemutanttranscriptatalevel56higherthanendogenousFig4completelyrescuedlethality, whereas26expressiongaveonlypartialrescue,providingamodelofthehumandisease.ThelevelofFIG4-I41Tproteinin transgenictissuesisonly2%ofthatpredictedbythetranscriptlevel,asaconsequenceoftheproteininstabilitycausedby impairedinteractionofthemutantproteinwithVAC14.Analysisofpatientfibroblastsdemonstratedacomparablylowlevel ofmutantI41Tprotein.TheabundanceofFIG4-I41Tproteininculturedcellsisincreasedbytreatmentwiththeproteasome inhibitorMG-132.ThedatademonstratethatFIG4-I41Tisahypomorphicalleleencodingaproteinthatisunstableinvivo. Expression of FIG4-I41T protein at 10% of normal level is sufficient for long-term survival, suggesting that patients with CMT4Jcouldbetreatedbyincreasedproductionorstabilizat