testing for familial pancreatitis家族性胰腺炎的诊断测试课件

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1、DiagnosticTestingforFamilialPancreatitisEmmaMcCarthyClinicalScientistMerseyside&CheshireRegionalMolecularGeneticsLaboratoryAimsOverviewofpancreatitisbothhereditaryandidiopathicGenesinvolved&diagnosticservicePRSS1dosageanalysisPancreatitisInflammatorydiseaseSevereabdominalpainNauseaVomitingfeverAcu

2、teorchronicPrematureactivationdigestiveenzymesCommontriggersExcessivealcoholconsumptionSmokingGallstonesTRYPSINOGENTRYPSINAUTODIGESTIONCHRONICPANCREATITISPERMANENTLOSSOFFUNCTIONDIABETES/PANCREATICCANCERmultipleattacksprematureactivationenzymesactivationirreversiblescarringadvancedstagesReproducedf

3、rom:Rosendahletal.OrphanetJournalofRareDiseases20072:1DiagnosticservicePRSS1Fluorescentsequencingexons2+3SPINK1p.N34Smutation(pyrosequencing)CFTR28mutations(ElucigeneCFHT)EUROPAC:www.liv.ac.uk/surgery/europac.htmlHereditaryPancreatitis(HP)AutosomaldominantReducedpenetranceChildhood:recurrentepisod

4、esacutepancreatitisAdulthood:chronicpancreatitisMutationsofcationictrypsinogengene(PRSS1)CationicTrypsinogenPRSS1gene(proteaseserine1)TrypsinActivatesdigestiveenzymesSelfregulatingAutocatalyticactivationFeedbackinhibition-cleavesatArg122R122Hmutation-“supertrypsin”PRSS1PRSS2TRY5TRY7TRY6TCRTCR4kbin

5、itialPCRproductN29IL41LC48Cp.N29Ic.86A>Tp.C48Cc.144T>Cp.L41Lc.121C>Tp.N54Sc.161A>Gp.V59Vc.177A>Gp.G62Gc.186C>TLaboratoryDataPrior2007:PCR/restrictiondigest-p.A16V,p.N29I,p.R122HFeb2007:fluorescentsequencingexons2&3Pathogenicmutationsdetected-7/77(9.1%)2/77unclassifiedvariantsTotalsequencechangesid

6、entified-9/77(11.7%)IdiopathicChronicPancreatitis(ICP)30%pancreatitiscases-unknowncauseSusceptibilitygenes:SPINK1-SerineProteaseInhibitorKazaltype1CFTR–mildmutations;ICPspecificmutations??polygenicmodelSPINK1Inhibits20%pancreatictrypsinp.N34Smutation22%ICPpatients2.5%generalpopulation?diseasemodif

7、ierSPINK1AnalysisPyrosequencingassayc.101A>G;p.N34S9/60mutationcarriers0/8CFTRmutationsnoCFtestingon1positivecaseNormal2copiesN34S1copyN34SPRSS1DosageAnalysisTriplicationoftrypsinogenlocusreportedLeMaréchaletal.,