OMIMResultMyNCBI[SignIn][Register]Entrez20All DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNP SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSforGoClearLimitsPreview/IndexHistoryClipboardDetails DisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksCoreNucleotideLinksESTLinksGSSLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboard*603201GeneTestsLinksATPBINDINGCASSETTESUBFAMILYBMEMBER11ABCB11AlternativetitlessymbolsBILESALTEXPORTPUMPBSEPSISTEROFPGLYCOPROTEINSPGPGenemaplocus2q24TEXTCLONINGBypositionalcloningwithinthecandidateregionforprogressiveintrahepaticcholestasis2(PFIC2601847)onchromosome2q24Strautnieksetal(1998)identifiedandclonedtheABCB11genewhichtheycalledBSEPThededucedproteinhasapredictedtopologysimilartothatofothermembersofthemultidrugresistant(MDR)familywith2putativetransmembranedomainseachwith6spansand2nucleotidebindingfoldscontaininghighlyconservedATPbindingcassettes(ABC)Northernblotanalysisdetecteda55kbmRNAtranscriptinliverGerloffetal(1998)hadidentifiedtherathomologdesignated'sisterofPglycoprotein'(Spgp)RatSpgpisexpressedonlyinthelivercanalicularmembraneInvitrostudiesshowedthatratSpgpisafunctionalbileacidtransporterMOLECULARGENETICSInpatientswithPFIC2Strautnieksetal(1998)identified10differentmutationsintheABCB11gene(seeeg60320100016032010004)FourmutationspredictedprematuretruncationoftheproteintheremainingmutationsweremissensechangesFiveofthemissensemutationswerefoundinconsanguineousfamiliesandtheaffectedindividualswereallhomozygotesThecombinationoftheinvitrofunctionalstudiesofratSpgpandthephenotypeseeninPFIC2patientsprovidedevidencethatABCB11isthemajorcanalicularbilesaltexportpumpinmanUsingimmunohistochemistryJansenetal(1999)foundabsenceoftheBSEPproteinin16of28liverbiopsysamplesfrompatientswithPFICAll10oftheBSEPnegativepatientstestedwerefoundtohavemutationsintheABCB11gene(seeeg6032010007)SixpatientshadheterozygousmutationsandJansenetal(1999)suggestedthattheseconddiseasecausingmutationshadnotyetbeenidentifiedVanMiletal(2004)identified8differentmutationsintheABCB11gene(seeeg6032010002)in11patientsfrom8familieswithbenignrecurrentintrahepaticcholestasis2(BRIC2605479)Homozygousandcompoundheterozygousmutationswereidentifiedin7patientsand3patientsrespectivelyOnepatienthadonlyaheterozygousmutationInapatientwithBRIC2Noeetal(2005)identifiedcompoundheterozygosityfor2mutationsintheABCB11gene(60320100026032010006)InvitrofunctionalexpressionstudiesshowedthatbothmutantproteinsretainedresidualtransportactivityconsistentwiththemilderphenotypeHepaticBSEPproteinexpressionwaspreservedinliverbiopsyfromthepatientKniselyetal(2006)studied11patientswithPFICinwhomhepatocellularcarcinomawasdiagnosedbetweentheagesof13and52monthsArchivalmaterialwasretrievedforstudyandleukocytesonpatientsandparentswerestudiedwhenavailableBSEPdeficiencywasdemonstratedbyimmunohistochemicalanalysisand13differentmutationsintheABCB11genewereidentifiedinallpatientsinwhomleukocyteDNAcouldbestudiedthesemutationswereconfirmedintheparentsKniselyetal(2006)concludedthatPFIC2causedbymutationsintheABCB11geneincreasestheriskofhepatocellularcarcinomainearlylifeANIMALMODELWangetal(2001)showedthatknockoutoftheSpgpgeneinmiceresultsinintrahepaticcholestasisbutwithsignificantlylessseveritythanPFIC2inhumansSomeunexpectedcharacteristicswereobservedNotablyalthoughthesecretionofcholicacidinmutantmicewasgreatlyreduced(6%ofwildtype)totalbilesaltoutputinmutantmicewasabout30%ofwildtypeAlsosecretionofanunexpectedlylargeamountoftetrahydroxylatedbileacids(notdetectedinwildtype)wasobservedTheseresultssuggestedthathydroxylationandanalternativecanaliculartransportmechanismforbileacidscompensatefortheabsenceofSpgpfunctionandprotectthemutantmicefromseverecholestaticdamage(selectedexamples)0001CHOLESTASISPROGRESSIVEFAMILIALINTRAHEPATIC2[ABCB11ARG575TER]InaffectedmembersofaLatinAmericanfamilysegregatingPFIC2(601847)Strautnieksetal(1998)identifiedhomozygosityfora1723CTtransitionintheABCB11generesultinginanarg575toter(R575X)substitutionInaffectedmembersofaBelgianfamilywithPFIC2themutationwasheterozygousandasecondABCB11mutationontheotherallelewasnotidentified0002CHOLESTASISPROGRESSIVEFAMILIALINTRAHEPATIC2[ABCB11GLU297GLY]CHOLESTASISBENIGNRECURRENTINTRAHEPATIC2INCLUDEDInaffectedmembersof7familiessegregatingPFIC2(601847)Strautnieksetal(1998)identifiedhomozygosityforan890AGtransitionintheABCB11generesultinginaglu297togly(E297G)substitutionintheintracellularloopbetweentransmembranespans4and5Affectedmembersof6otherfamilieshadaheterozygousE297GmutationbutasecondABCB11mutationontheotherallelewasnotidentifiedInapatientwithPFIC2Jansenetal(1999)identifiedcompoundheterozygosityfor2mutationsintheABCB11geneE297GandR1057X(6032010007)ImmunohistochemistryshowedabsenceoftheBSEPproteininliverVanMiletal(2004)identifiedhomozygosityfortheE297Gmutationin2unrelatedpatientswithbenignrecurrentintrahepaticcholestasis2(605479)BothpatientshadnumerousepisodesanddevelopedpermanentcholestasislaterinlifeIna16yearoldboywithbenignrecurrentintrahepaticcholestasis2Noeetal(2005)identifiedcompoundheterozygosityfor2mutationsintheABCB11geneE297GandR432T(6032010006)InvitrofunctionalexpressionstudiesshowedthattheE297GandR432Tmutantproteinshad20%and13%transportactivityrespectivelycomparedtowildtype0003CHOLESTASISPROGRESSIVEFAMILIALINTRAHEPATIC2[ABCB111BPDEL908G]InaffectedmembersofaPolishfamilysegregatingPFIC2(601847)Strautnieksetal(1998)identifiedaheterozygous1bpdeletion(908delG)intheABCB11generesultinginachangeofaminoacid303andtheintroductionof17novelaminoacidsfollowedbytruncationoftheprotein0004CHOLESTASISPROGRESSIVEFAMILIALINTRAHEPATIC2[ABCB111BPINS3767C]InaffectedmembersofafamilysegregatingPFIC2(601847)Strautnieksetal(1998)identifiedahomozygous1bpinsertion(3767insC)intheABCB11generesultinginachangeinaminoacid1256withtheintroductionof39novelaminoacidsfollowedbytruncationoftheprotein0004CHOLESTASISPROGRESSIVEFAMILIALINTRAHEPATIC2[ABCB11IVS4DSAC+3]InapatientwithPFIC2(601847)Noeetal(2005)identifiedcompoundheterozygosityfor2mutationsintheABCB11geneanAtoCtransversioninintron4resultinginasplicesitemutationanda5bpinsertioninexon21resultinginaframeshiftandprematuretruncationoftheprotein(6032010005)Eachunaffectedparentwasheterozygousfor1ofthemutationsImmunohistochemicalstainingrevealedcompleteabsenceofhepaticBSEPexpressioninthepatient0005CHOLESTASISPROGRESSIVEFAMILIALINTRAHEPATIC2[ABCB115BPINSGAGAT]See6032010004andNoeetal(2005)0006CHOLESTASISBENIGNRECURRENTINTRAHEPATIC2[ABCB11ARG432THR]Ina16yearoldboywithbenignrecurrentintrahepaticcholestasis2(605479)Noeetal(2005)identifiedcompoundheterozygosityfor2mutationsintheABCB11genea1296GCtransversioninexon12resultinginanarg432tothr(R432T)substitutionandE297G(6032010002)Eachunaffectedparentwasheterozygousfor1ofthemutationsThepatientpresentedwithahistoryofintermittentepisodesofpruritusandsteatorrheaforseveralyearsCholestaticepisodeswerereportedlytriggeredbyinfectionsorintakeofcertainmedicationsLiverbiopsyshowedmildhepatocellularandcanalicularcholestasiswithoutportalfibrosisInvitrofunctionalexpressionstudiesshowedthattheE297GandR432Tmutantproteinshad20%and13%transportactivityrespectivelycomparedtowildtype0007CHOLESTASISPROGRESSIVEFAMILIALINTRAHEPATIC2[ABCB11ARG1057TER]InapatientwithPFIC2(601847)Jansenetal(1999)identifiedcompoundheterozygosityfor2mutationsintheABCB11genearg1057toter(R1057X)andE297G(6032010002)ImmunohistochemistryshowedabsenceoftheBSEPproteininliverSEEALSOSandoretal(1976)REFERENCES1GerloffTStiegerBHagenbuchBMadonJLandmannLRothJHofmannAFMeierPJThesisterofPglycoproteinrepresentsthecanalicularbilesaltexportpumpofmammalianliverJBiolChem27310046100501998PubMedID95453512JansenPLMStrautnieksSSJacqueminEHadchouelMSokalEMHooiveldGJEJKoningJHDeJagerKrikkenAKuipersFStellaardFBijleveldCMAGouwAVanGoorHThompsonRJMullerMHepatocanalicularbilesaltexportpumpdeficiencyinpatientswithprogressivefamilialintrahepaticcholestasisGastroenterology117137013791999PubMedID105799783KniselyASStrautnieksSSMeierYStiegerBByrneJAPortmannBCBullLNPawlikowskaLBilezikciBOzcayFLaszloATiszlaviczLand14othersHepatocellularcarcinomaintenchildrenunderfiveyearsofagewithbilesaltexportpumpdeficiencyHepatology444784862006PubMedID168715844NoeJKullakUblickGAJochumWStiegerBKerbRHaberlMMullhauptBMeierPJPauliMagnusCImpairedexpressionandfunctionofthebilesaltexportpumpduetothreenovelABCB11mutationsinintrahepaticcholestasisJHepatol435365432005PubMedID160397485SandorTSurinyaMMonusZFamilialoccurrenceofgiantcellhepatitisininfancyActaHepatoGastroent2310110419766StrautnieksSSBullLNKniselyASKocoshisSADahlNArnellHSokalEDahanKChildsSLingVTannerMSKagalwallaAFNemethAPawlowskaJBakerAMieliVerganiGFreimerNBGardinerRMThompsonRJAgeneencodingaliverspecificABCtransporterismutatedinprogressivefamilialintrahepaticcholestasisNatureGenet202332381998PubMedID98065407vanMilSWCvanderWoerdWLvanderBruggeGSturmEJansenPLMBullLNvandenBergIETBergerRHouwenRHJKlompLWJBenignrecurrentintrahepaticcholestasistype2iscausedbymutationsinABCB11Gastroenterology1273793842004PubMedID153005688WangRSalemMYousefIMTuchweberBLamPChildsSJHelgasonCDAckerleyCPhillipsMJLingVTargetedinactivationofsisterofPglycoproteingene(spgp)inmiceresultsinnonprogressivebutpersistentintrahepaticcholestasisProcNatAcadSci98201120162001PubMedID11172067CONTRIBUTORSVictorAMcKusickupdated9/12/2006CassandraLKniffinupdated6/19/2006CassandraLKniffinreorganized6/15/2006VictorAMcKusickupdated3/6/2001CREATIONDATEVictorAMcKusick10/26/1998EDITHISTORYcarol10/2/2006ckniffin9/25/2006terry9/12/2006carol6/21/2006ckniffin6/19/2006carol6/15/2006ckniffin2/27/2006mcapotos3/12/2001terry3/6/2001carol11/9/1999dkim11/13/1998alopez10/28/1998alopez10/26/1998alopez10/26/1998Copyright©19662007JohnsHopkinsUniversityDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIHÂ