Ganglioside GM3 Levels Are Altered in a Mouse Model of HIBM GM3 as a Cellular Marker of the Disease 英文参考文献.docVIP

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Ganglioside GM3 Levels Are Altered in a Mouse Model of HIBM GM3 as a Cellular Marker of the Disease 英文参考文献.doc

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Ganglioside GM3 Levels Are Altered in a Mouse Model of HIBM GM3 as a Cellular Marker of the Disease 英文参考文献

GangliosideGM3LevelsAreAlteredinaMouseModelof HIBM:GM3asaCellularMarkeroftheDisease ThomasPaccalet,Zoe′ Coulombe,JacquesP.Tremblay* CentredeRechercheduCentreHospitalierUniversitairedeQue′bec-Unite′ deGe′ne′tique Humaine,Universite′ Laval,Que′bec,Canada Abstract Objective:HIBM(HereditaryInclusionBodyMyopathy)isarecessivehereditarydiseasecharacterizedbyadult-onset,slowly progressivemuscleweaknesssparingthequadriceps.ItiscausedbyasinglemissensemutationofeachalleleoftheUDP-N- acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, a bifunctional enzyme catalyzing the first two stepsofsialicacidsynthesisinmammals.However,themechanismsandcellularpathwaysaffectedbytheGNEmutation andcausingthemuscleweaknesscouldnotbeidentifiedsofar.Basedonrecentevidenceinliterature,weinvestigateda newhypothesis,i.e.theinvolvementinthediseaseoftheGM3ganglioside,aspecificglycolipidimplicatedinmusclecell proliferationanddifferentiation. Methods:qRT-PCRanalysisofSt3gal5(GM3synthase)geneexpressionandHPLCquantificationofGM3gangliosidewere conductedonmuscletissuefromamousemodelofHIBMharboringtheM712TmutationofGNE(GneM712T/M712T mouse)vs controlmice(Gne+/+ mouse). Results: St3gal5 mRNA levels were significantly lower in GneM712T/M712T mouse muscles vs Gne+/+ mouse muscles +/+ (64.41%610%ofGne levels).GM3gangliosidelevelsshowedalsoasignificantdecreaseinGneM712T/M712T mousemuscle comparedtoGne+/+mousemuscle(18.09%65.33%ofGne+/+levels).AlthoughtheseGneM712T/M712T miceweredescribedto suffersevereglomerularproteinuria,noGM3alterationswerenotedinkidneys,highlightingatissuespecificalterationof gangliosides. Conclusion:TheM712TmutationofGNEhampersthemuscleabilitytosynthesizenormallevelsofGM3.Thisisthefirst timethatamutationofGNEcanberelatedtothemolecularpathologicalmechanismofHIBM. Citation: Paccalet T, Coulombe Z, Tremblay JP (2010) Ganglioside GM3 Levels Are Altered in a Mouse Model of HIBM: GM3 as a Cellular Marker of the Disease.PLoSONE5(4):e10055.doi:10.1371/jo