Protein Misfolding as an Underlying Molecular Defect in Mucopolysaccharidosis III Type C 英文参考文献.docVIP

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Protein Misfolding as an Underlying Molecular Defect in Mucopolysaccharidosis III Type C 英文参考文献.doc

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Protein Misfolding as an Underlying Molecular Defect in Mucopolysaccharidosis III Type C 英文参考文献

ProteinMisfoldingasanUnderlyingMolecularDefectin MucopolysaccharidosisIIITypeC MatthewFeldhammer1,2.,Ste′phanieDurand1.,AlexeyV.Pshezhetsky1,2,3,4 * 1DepartmentofMedicalGenetics,CHUSainte-JustineUniversityofMontreal,Montreal,Canada,2DepartmentofBiochemistry,UniversityofMontreal,Montreal,Canada, 3DepartmentofPediatrics,UniversityofMontreal,Montreal,Canada,4DepartmentofAnatomyandCellBiology,FacultyofMedicine,McGillUniversity,Montreal,Canada Abstract MucopolysaccharidosistypeIIICorSanfilipposyndrometypeC(MPSIIIC,MIM#252930)isanautosomalrecessivedisorder causedbydeficiencyofthelysosomalmembraneenzyme,heparansulfateacetyl-CoA:a-glucosaminideN-acetyltransferase (HGSNAT,EC8),whichcatalysestransmembraneacetylationoftheterminalglucosamineresiduesofheparansulfate prior to their hydrolysis by a-N-acetylglucosaminidase. Lysosomal storage of undegraded heparan sulfate in the cells of affected patients leads to neuronal death causing neurodegeneration and is accompanied by mild visceral and skeletal abnormalities,includingcoarsefaciesandjointstiffness.Surprisingly, themajorityofMPSIIICpatientscarrying missense mutations are as severely affected as those with splicing errors, frame shifts or nonsense mutations resulting in the complete absence of HGSNAT protein. In order to understand the effects of the missense mutations in HGSNAT on its enzymaticactivityandbiogenesis,wehaveexpressed21mutantproteinsinculturedhumanfibroblastsandCOS-7cellsand studiedtheirfolding,targetingandactivity.Wefoundthat17ofthe21missensemutationsinHGSNATcausedmisfoldingof theenzyme,whichisabnormallyglycosylatedandnottargetedtothelysosome,butretainedintheendoplasmicreticulum. Theother4mutantsrepresentedrarepolymorphismswhichhadnoeffectontheactivity,processingandtargetingofthe enzyme. Treatment of patient cells with a competitive HGSNAT inhibitor, glucosamine, partially rescued several of the expressed mutants. Altogether our data provide an explanation for the severity of MPS IIIC and suggest that sear