Alternative Splicing and Extensive RNA Editing of Human TPH2 Transcripts 英文参考文献.docVIP

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Alternative Splicing and Extensive RNA Editing of Human TPH2 Transcripts 英文参考文献.doc

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Alternative Splicing and Extensive RNA Editing of Human TPH2 Transcripts 英文参考文献

AlternativeSplicingandExtensiveRNAEditingofHuman TPH2Transcripts MaikGrohmann1,2,3,PaulHammer1,MariaWalther1,NilsPaulmann1,2,AndreasBu¨ttner4 ,Wolfgang Eisenmenger4,ThomasC.Baghai6,CorneliusSchu¨le6,RainerRupprecht6,MichaelBader5 ,Brigitta Bondy6,PeterZill6,JosefPriller3.,DiegoJ.Walther1*. 1Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany, 2Department of Biology, Chemistry, and Pharmacy, Free UniversityBerlin,Berlin,Germany,3NeuropsychiatryandLaboratoryofMolecularPsychiatry,Charite′-Universita¨tsmedizin,Berlin,Germany,4InstituteforLegalMedicine, LudwigMaximiliansUniversity,Munich,Germany,5LaboratoryofMolecularBiologyofPeptideHormones,MaxDelbru¨ckCenterforMolecularMedicine,Berlin,Germany, 6DepartmentofPsychiatry,LudwigMaximiliansUniversity,Munich,Germany Abstract Brainserotonin(5-HT)neurotransmissionplaysakeyroleintheregulationofmoodandhasbeenimplicatedinavarietyof neuropsychiatricconditions.Tryptophanhydroxylase(TPH)istherate-limitingenzymeinthebiosynthesisof5-HT.Recently, wediscoveredasecondTPHisoform(TPH2)invertebrates,includingman,whichispredominantlyexpressedinbrain,while thepreviouslyknownTPHisoform(TPH1)isprimarlyanon-neuronalenzyme.OverwhelmingevidencenowpointstoTPH2 as a candidate gene for 5-HT-related psychiatric disorders. To assess the role of TPH2 gene variability in the etiology of psychiatricdiseasesweperformedcDNAsequenceanalysisofTPH2transcriptsfromhumanpostmortemamygdalasamples obtainedfromindividualswithpsychiatricdisorders(drugabuse,schizophrenia,suicide)andcontrols.Hereweshowthat TPH2 exists in two alternatively spliced variants in the coding region, denoted TPH2a and TPH2b. Moreover, we found evidencethatthepre-mRNAsofbothsplicevariantsaredynamicallyRNA-editedinamutuallyexclusivemanner.Kinetic studieswithcelllinesexpressingrecombinantTPH2variantsrevealedahigheractivityofthenovelTPH2Bproteincompared withthepreviouslyknownTPH2A,whereasRNAeditingwasshowntoinhibittheenzymaticactivityofbothTPH2spl