OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP1OMIMUniSTS0+107730GeneTestsLinksAPOLIPOPROTEINBAPOBAlternativetitlessymbolsAPOB100INCLUDEDAPOB48INCLUDEDAPOLIPOPROTEINBALLOTYPESINCLUDEDAgLIPOPROTEINTYPESINCLUDEDHYPOBETALIPOPROTEINEMIAFAMILIALINCLUDEDFHBLINCLUDEDHYPOBETALIPOPROTEINEMIAFAMILIAL1INCLUDEDFHBL1INCLUDEDACANTHOCYTOSISWITHHYPOBETALIPOPROTEINEMIAINCLUDEDHYPOBETALIPOPROTEINEMIANORMOTRIGLYCERIDEMICINCLUDEDGenemaplocus2p24TEXTApolipoproteinBisthemainapolipoproteinofchylomicronsandlowdensitylipoproteins(LDL)Itoccursintheplasmain2mainformsapoB48andapoB100ThefirstissynthesizedexclusivelybythegutthesecondbytheliverLusisetal(1985)identifiedcDNAclonesforhumanapoBexaminationofasomaticcellpanelindicatedthattheAPOBgeneresidesonchromosome2unlinkedtothe3otherapolipoproteinclustersLawetal(1985)clonedthegeneandassignedittochromosome2byfilterhybridizationwithDNAfromhuman/mousesomaticcellhybridsBysomaticcellhybridstudiesandbyinsituhybridizationKnottetal(1985)assignedthegenetothetipof2pinbandp24Deebetal(1986)usedahybridizationprobetodetecthomologoussequencesinbothflowsortedandinsitumetaphasechromosomesThegenewasassignedto2p24p23TheyfoundfurthermorethatRNAisolatedfrommonkeysmallintestinecontainedsequenceshomologoustothecDNAofapolipoproteinB100Theseresultswereinterpretedasindicatingthatintestinal(B48)andhepatic(B100)formsofapoBarecodedbyasinglegeneGlickmanetal(1986)foundasinglemRNAtranscriptforapoBregardlessoftheformofapoB(apoB100orapoB48)synthesizedintheliverorintestineFromstudyofchromosomalaberrationsinsomaticcellhybridsHuangetal(1986)concludedthattheAPOBlocusislocatedineitherthe2p21p23orthe2pterp24segmentMehrabianetal(1986)localizedAPOBto2p24p23bysomaticcellhybridizationandinsituhybridizationFilterhybridizationstudieswithgenomicDNAandwithhepaticandintestinalmRNAsuggestedthathepaticandintestinalapoBarederivedfromthesamegeneHospattankaretal(1986)presentedsomeimmunologicdatasuggestingthatthe2proteinsshareacommoncarboxylregionsequenceChenetal(1986)determinedthecompletecDNAandaminoacidsequenceofapoB100Knottetal(1986)reportedtheprimarystructureofapolipoproteinBTheprecursorhas4563aminoacidsthematureapoB100has4536aminoacidresiduesThisrepresentsaverylargemRNAofmorethan16kbLawetal(1986)alsoprovidedthecompletenucleotideacidandderivedaminoacidsequenceofapoB100fromastudyofcDNAStrongevidencethatapoB100andapoB48areproductsofthesamegenewasprovidedbyYoungetal(1986)TheyusedaspecificmousemonoclonalantibodyMB19tocharacterizeacommonformofgeneticpolymorphismofAPOBTheyfoundthatthepolymorphismwasexpressedinaparallelmannerinapoB100andapoB48Cladarasetal(1986)concludedfromthesequenceofapolipoproteinB100thatapoB48mayresultfromdifferentialsplicingofthesameprimaryapoBmRNAtranscriptHardmanetal(1987)foundthatmaturecirculatingB48ishomologousoveritsentirelength(estimatedtobebetween2130and2144aminoacidresidues)withtheaminoterminalportionofB100andcontainsnosequencefromthecarboxylendofB100FromstructuralstudiesInnerarityetal(1987)concludedthatapoB48representstheaminoterminal47%ofapoB100andthatthecarboxylterminusofapoB48isinthevicinityofresidue2151ofapoB100Chenetal(1987)deducedthathumanapolipoproteinB48istheproductofanintestinalmRNAwithaninframeUAAstopcodonresultingfromaCtoUchangeinthecodonCAAencodingGln(2153)inapoB100mRNAThecarboxylterminalile2152ofapoB48purifiedfromchylousascitesfluidhasapparentlybeencleavedfromtheinitialtranslationproductleavingmet2151asthenewcarboxylterminusTheorganspecificintroductionofastopcodontoanmRNAisanunprecedentedfindingOnlythesequencethatcodesB100ispresentingenomicDNAThechangefromCAAtoUAAascodon2153ofthemessageisauniqueRNAeditingprocessHiguchietal(1988)reportedsimilarfindingsApoB48contains2152residuescomparedto4535residuesinapoB100UsingaclonedratcDNAasaprobeLauetal(1994)clonedcDNAandgenomicsequencesofthegeneforthehumanAPOBmRNAeditingprotein(BEDP600130)ExpressionofthecDNAinHepG2cellsresultedineditingoftheintracellularapoBmRNAByfluorescenceinsituhybridizationtheylocalizedtheBEDPgeneto12p132p131ByNorthernblotanalysistheyshowedthatthehumanBEDPmRNAisexpressedexclusivelyinthesmallintestineThecDNAsequencepredictedatranslationproductof236aminoacidresiduesTheyfoundthattheeditingproteinundergoesspontaneouspolymerizationandexistsasadimerTheeditingproteinisacytidinedeaminaseshowingstructuralhomologytootherknownmammalianandbacteriophagedeoxycytidylatedeaminasesSteinbergetal(1979)describedakindredwithanewformofhypobetalipoproteinemiacharacterizedbyunusuallylowLDLcholesterolnormaltriglyceridelevelslowlevelsofHDLmildfatmalabsorptionandadefectinchylomicronclearanceOnahighcarbohydratedietthetriglyceridelevelsofthe67yearoldprobandfellratherthanroseTheprobandaretiredNavalchaplainwasasymptomaticHecametoattentionbecauseoftotalserumcholesterolof47mg/dlTheproband'smotheraged921brother1sisterand2daughtersalsohadhypobetalipoproteinemiaYoungetal(1987)foundanabnormalityofapoBcalledapolipoproteinB37intheplasmalipoproteinsofmultiplemembersofthiskindredYoungetal(1987)reportedanintensivestudyof41membersin3generationsofthiskindredTheydocumentedthepresenceinadditiontotheabnormaltruncatedapoBspeciesB37ofanotherapoBallelethatwasassociatedwithreducedplasmaconcentrationsofthenormalapoB100Theproband(HJB)and2ofhissibshadbothabnormalapoBallelesandwerethereforecompoundheterozygotesforfamilialhypobetalipoproteinemiaAlloftheoffspringofthe3compoundheterozygoteshadhypobetalipoproteinemiaandeachhadevidenceofonly1oftheabnormalapoBallelesTheaverageLDLcholesterollevelswereinthecompoundheterozygotes6mg/dlinthe6heterozygoteswhohadonlytheabnormalapoB37allele31mg/dlinthe10heterozygoteswhohadonlythealleleforreducedplasmaconcentrationsofapoB10031mg/dlandin22unaffectedfamilymembers110mg/dlLawetal(1986)foundthat60of83middleagedwhitemenhadanXbaIrestrictionsitepolymorphismwithinthecodingsequenceoftheapoBgenePersonshomozygousorheterozygousfortheXbaIrestrictionsitehadmeanserumtriglyceridelevels36%higherthanhomozygoteswithoutthesiteMeanserumcholesterolwaslessstrikinglyelevatedinthosewiththerestrictionsiteTheAgsystemoflipoproteinantigens(seelater)isknowntorepresentpolymorphismoftheAPOBlocusItisinstronglinkagedisequilibriumwiththeXbaIRFLPthe2probablyrevealthesameassociationwithplasmalipidsMehrabianetal(1986)alsoidentified2commonRFLPswhichshouldbeusefulinfamilystudiesAntonarakis(1987)andhiscolleaguesidentifiedamissensepointmutationintheAPOBgeneassociatedwithhyperbetalipoproteinemiaThemutationoccurredatapotentialsiteofbindingofAPOBtoLDLRandapparentlyresultedininterferencewiththemetabolismofapolipoproteinBThefindingofnorecombinationbetweenthehypobetalipoproteinemiaphenotypeandaparticularDNAhaplotypeoftheAPOBgene(Leppertetal1988)indicatedthatatleastinthefamilystudiedhypobetalipoproteinemiawastheresultofamoleculardefectinapolipoproteinBSinghetal(2004)examinedtheassociationbetweentheXbaIpolymorphismofAPOB100andgallbladderdiseasesincludinggallbladdercancerinanonIndianpopulationinwhichbothgallstonesandgallbladdercancerarecommonTheyfoundthatthefrequencyofXallelewassignificantlyincreasedingallbladdercancerpatientswithorwithoutgallstones(oddsratio=23and17respectively)TheysuggestedthattheapoBXbaIgenepolymorphismconferssusceptibilitytocarcinomaofthegallbladderunderspecificenvironmentalconditionsKeidaretal(1990)describedapparentcompoundheterozygosityforabetalipoproteinemia(200100)andfamilialhypobetalipoproteinemiaThefindingindicatedthatabetalipoproteinemiamaylikehypobetalipoproteinemiabeduetoamutationintheAPOBgeneTheprobanda10yearoldboywithabetalipoproteinemiahadafatherwithanormalapolipoproteinprofilehoweverhismotherandmaternalgrandfathersufferedfromfamilialhypobetalipoproteinemiaTalmudetal(1988)presentedevidencethatthedefectinabetalipoproteinemia(atleastinthe2familiesstudied)doesnotinvolvetheAPOBgeneineachofthese2families2affectedchildreninheriteddifferentAPOBRFLPallelesfromatleast1parentwhereasthesibswouldbeanticipatedtosharecommonallelesifthisdisorderwereduetoanAPOBmutationDemantetal(1988)foundasignificantassociationbetweenaparticularRFLPoftheAPOBgeneandthetotalfractionalclearancerateofLDLPresumablythiseffectactsthroughvariablebindingtotheLDLRandisasignificantfactorintherateofcatabolismofLDLCorsinietal(1989)describedfamilialhypercholesterolemia(FH)duenottoadefectintheLDLRasinconventionalFH(143890)buttobindingdefectiveLDLpresumablyfamilialdefectiveapoB100RajputWilliamsetal(1988)demonstratedassociationofspecificallelesfortheapoBgenewithobesityhighbloodcholesterollevelsandincreasedriskofcoronaryarterydiseaseSeveraloftheRFLPsusedasmarkersdonotchangetheaminoacidsequenceTheauthorsconcludedthattheseRFLPsareinlinkagedisequilibriumwithnearbyfunctionalvariationpredisposingtoobesityorincreasedriskofcoronaryarterydiseaseVariationsinserumcholesterollevelwereassociatedwith3functionalallelescorrespondingtoaminoacidvariantsatpositions3611and4154bothofwhichlieneartheLDLRbindingregionofapoBProductsoftheAPOBgenewithhighorlowaffinityfortheMB19monoclonalantibodycanbedistinguishedGavishetal(1989)usedthisantibodytoidentifyheterozygotesanddetectallelespecificdifferencesintheamountofAPOBintheplasmaAfamilystudyconfirmedthattheunequalexpressionphenotypewasinheritedinanautosomaldominantmannerandwaslinkedtotheAPOBlocusBrownetal(1974)notedthattheconsistentlaboratoryfindingsofreducedserumcholesterolandbetalipoproteindefinehypobetalipoproteinemiaasadistinctsyndromeTheyfound4reportedkindredsandaddedafifthOnly2ofthepatientsinthereportedfamilieshadsymptomsMarsetal(1969)observedafamilyinwhich1ofthe14hypobetalipoproteinemicpersons(in3generations)a37yearoldwomanhadsignsandsymptomsofprogressivedemyelinationofthecentralnervoussystemlackofresponsivenesstolocalanesthesiaanddislikeforanimalfatsandmilkThefamilyreportedbyBrownetal(1974)containedachildwithpsychomotorretardationAlthoughtheperipheralbloodsmearshowednoacanthocytestheredcellsonsymptomaticandasymptomaticpersonsbecameacanthocytoticwhenplacedintissueculturemediumwith10%autologousserumBiemerandMcCammon(1975)describedafamilyandreviewedothersintheliteratureinwhichapersonwith'homozygoushypobetalipoproteinemia'hadoccurredTheypointedoutthatalthoughsomeofthesecasesweremilderthancasesofabetalipoproteinemiahomozygoushypobetalipoproteinemiacouldoftenbedistinguishedfromabetalipoproteinemiaonlybythedemonstrationofpresumablyheterozygoushypobetalipoproteinemicfirstdegreerelativesofthehomozygoteThismaynotindicatethatthesearedeterminedbydifferentlociitmaybeasituationlikethe3probablyallelicformsofcystinuria(220100)whicharedistinguishableonlybywhetheraminoaciduriaisdemonstrableinheterozygotesKahnandGlueck(1978)reportedremarkablefreedomfromatheromaina76yearoldwomanwhodiedfromhepaticfailuredueapparentlytohemochromatosisThewomanhadbeenfoundtohavehypobetalipoproteinemiainastudydonepreviously(Gluecketal1976)Thisandhyperalphalipoproteinemia(143470)areaccompaniedbyincreasedlifeexpectancyBergeretal(1983)studiedakindredinwhichtheprobandmanifestedtheclinicalandbiochemicalfeaturesofthehomozygousstateUnliketheapparentabsenceofapolipoproteinBintheplasmain5previouscasesofhomozygoushypobetalipoproteinemiatheyfoundaminuteamountofapoB(about0025%ofnormal)intheplasmaandsuggestedthatthedisordermightresultnotfromastructuralgenedefectbutfromafailureofsecretion(Iwouldinterpretthisfindingassupportingratherthanrefutingthestructuralmutationidea)SinceLDLsareamainsourceofcholesterolforsteroidhormoneformationParkeretal(1986)wereinterestedinstudyingtheendocrinechangesduringpregnancyinhomozygousfamilialhypobetalipoproteinemiaTheyfounditsurprisingthatthewomanwithphenotypicabetalipoproteinemiacouldbecome'pregnantletalonecarrythepregnancytotermwithouthormonaltherapy'Theynotedsuccessfulpregnancyin3otherabetalipoproteinemicwomenHaranoetal(1989)identifiedhomozygoushypobetalipoproteinemiain3sibsBothparentsand2childrenof1ofthesibswereheterozygousThe75yearoldprobandthefatherofthe3sibsdiedoffeverofunknowncausethrombocytopeniaandanemiaHehadataxicmovementsofthehandsandgaitdisturbanceinlaterlifeThe3homozygotesshowedmarkeddeficiencyofapoB100althoughtraceamountswerenotedinLDLIncontrastapoB48waspresentinchylomicronsobtainedafterafattymealin2ofthepatientswithhomozygoushypobetalipoproteinemiaindicatingaselectivedeficiencyofapoB100In2patientswithhomozygoushypobetalipoproteinemiaRossetal(1988)foundthatSouthernblotanalysiswith10differentcDNAprobesrevealedanormalgenewithoutmajorinsertionsdeletionsorrearrangementsNorthernandslotblotanalysesoftotallivermRNAshowedanormalsizedapoBmRNAthatwaspresentingreatlyreducedquantitiesApoBproteinwasdetectedinlivercellsimmunohistochemicallybutwasmarkedlyreducedinquantityandnoapoBwasdetectableintheplasmawithanELISAassayRossetal(1988)interpretedthefindingsasindicatingamutationinthecodingportionoftheapoBgeneleadingtoanabnormalapoBproteinandapoBmRNAinstabilityThesefindingswerequitedistinctfromthosepreviouslynotedinabetalipoproteinemia(200100)whichischaracterizedbyanelevatedlevelofhepaticapoBmRNAandaccumulationofintracellularhepaticapoBproteinThebloodlipidchangesthataccompanyheterozygoushypobetalipoproteinemiaarereducedplasmaconcentrationsofLDLcholesteroltotaltriglyceridesandAPOBtolessthan50%ofnormalvaluesLeppertetal(1988)foundthataDNAhaplotypeoftheAPOBgenecosegregatedwiththephenotypeinanIdahopedigreewithamaximumlodscoreof756attheta=00ThisfindingstronglysuggeststhatamutationintheAPOBgeneunderlieshypobetalipoproteinemiaandindicatestheusefulnessofthecandidategeneapproachAsindicatedinthelistingofallelicvariantsanumberofmutationsresultinginatruncatedapolipoproteinBhavebeenfoundasthebasisofhypobetalipoproteinemiaOntheotherhandotherpatientswiththisdisorderhavebeenfoundtohavereducedconcentrationsofafulllengthapoB100(Youngetal1987Bergeretal1983Gavishetal1989)Thistypeofgenedefectmayprovetobeanalogoustobeta(+)thalassemiawhichhasbeenshowntobecausedbypromotermutationsintronexonsplicingerrorsormutationinthepolyadenylationsignalArakietal(1991)describeda55yearoldmanwithcerebellarataxiadueapparentlytohypobetalipoproteinemiaAbrotheralsohadhypobetalipoproteinemiawithneurologicsymptomsThe2childrenoftheprobandaged31and29yearsandasisteroftheprobandhadonlyhypobetalipoproteinemiaTheprobandandhisneurologicallyaffectedbrotheraswellasmembersofthe2previousgenerationshadsteatocystomamultiplex(184500)ThelatterconditionmayhavebeencoincidentalAllisonandBlumberg(1961)andBlumbergetal(1963)describedapolymorphicsystemincludingserumbetalipoproteindistinctfromthatdiscoveredbyBergandMohranddesignatedLp(a)(see152200)TheydetectedthisbythestudyofpatientswhohadreceivedmultipletransfusionsThefirsttypewascalledAgathesecondwascalledAgbBlumbergetal(1964)proposedthesymbolLPforlipoproteinLowercaselettersareusedfordesignatingdifferentloci(ieLPaLPbLPcetc)andsuperscriptnumbersforallelesatthelocus(ieLPa1LPa2etc)RetentionoftheAgdesignationmaybeadvisabletoavoidconfusionwiththeBergtypeJacksonetal(1974)observedafamilyinwhichvariationofachromosome21appearedtobelinkedwithAgtypeThepeaklodscorewas21atarecombinationfractionof00Bergetal(1975)ontheotherhandfoundconsiderablerecombinationwithIPOA(147450)infamilystudiesIPOAisknowntobeonchromosome21fromhybridcellstudiesBergetal(1976)showedthatserumcholesterolandtriglyceridelevelswerehigherinAg(x)thaninAg(x+)personsThusasmallbutsignificanteffectofasingleautosomallocusinatherogenesismayhavebeendemonstratedMorgantietal(1975)indicatedthatthereareatleast5closelylinkedlociThisserumproteinpolymorphismwasdiscoveredbyBlumbergonthebasisofhishypothesisthatmultitransfusedpatientsshouldhaveantibodiesagainstpolymorphicserumproteinsTheAustraliaantigenwasfoundintheprocessofthesamestudiesapplyingtheadditionalprinciplethatthewidertheanthropologicspreadofseratested(egAustralianaborigines)thegreaterthelikelihoodoffindingapolymorphismOfcoursetheAustraliaantigenprovedtobenotapolymorphismbutaviremiaanevenmoreimportantdiscoveryasrecognizedbytheNobelPrizeBythisapproachBlumberg(1978)foundotherapparentpolymorphismsthathehasnotyetfullystudiedAllotypicvariationinLDLcomparabletoAghasbeenfoundinmostspeciesstudiedBergetal(1986)demonstratedcloselinkageoftheAgallotypesofLDLandDNApolymorphismsattheAPOBlocusLinkagedisequilibrium(allelicassociation)wasfoundbetweentheAgpolymorphismand2ofthe3DNApolymorphismsstudiedXuetal(1989)demonstratedthataparticularAgepitope(h/i)isdeterminedbyanargininetoglutaminesubstitutionatresidue3611ofthematureproteinTheaminoaciddifferenceresultsfromaCGGtoCAGchangeandcauseslossofanMspIrestrictionsiteBreguetetal(1990)foundthatwiththeexceptionoftheAmerindianstheAgsystemishighlypolymorphicinpopulationsworldwideTheysuggestedthatthesystemhasevolvedasaneutralornearlyneutralpolymorphismandisthereforehighlyinformativefor'modernhumanpeoplinghistory'studiesFollowingthecloningofthehumanAPOBgenenucleotidesubstitutionswerereportedascandidatesforthemolecularbasisofalltheAgepitopes(reviewedbyDunningetal1992)Dunningetal(1992)foundcompletelinkagedisequilibriumbetweentheimmunochemicalpolymorphismofLDLthatisdesignatedantigengroupAg(x/y)andtheallelesat2sitesinthematureapoB100moleculepro2712toleuandasn4311toserItappearedthattheAg(y)epitopewasassociatedwithasparagine4311plusproline2712whereasthealleleencodingserine4311plusleucine2712representedtheAg(x)epitopeIn4differentpopulationgroupstheyfoundcompleteassociationbetweenthesitesencodingresidues2712and4311althoughtherewerelargeallelefrequencydifferencesbetweenthesepopulationsInadditiontherewasstronglinkagedisequilibriumwithallelicassociationbetweentheallelesofthesesitesandthoseoftheXbaIRFLPinallpopulationsexaminedTakentogetherthesedatasuggestthattherehasbeenlittleornorecombinationinthe3primeendofthehumanAPOBgenesincethedivergenceofthemajorethnicgroupsLudwigetal(1989)describedahypervariableregion3primetothehumanAPOBgeneByPCRamplificationoftheregionfollowedbyelectrophoresisinadenaturingacrylamidegeltheyfound14differentallelescontaining25to52repeatsofa15basepairunitin318unrelatedindividualsBoerwinkleetal(1989)alsomadeobservationsonthisvariablenumberoftandemrepeats(VNTR)polymorphismBoehnke(1991)usedtheVNTRpolymorphismneartheAPOBlocusasatestcaseforhismethodofestimatingallelefrequencyfromdataonrelativesHestatedthatthereare15knownAPOBVNTRallelesandthat12wereobservedinthefamilieshestudiedByuseofbothpedigreelinkageanalysisandsibpairlinkageanalysisin23informativefamiliesCoreshetal(1992)foundnoevidenceofcommonAPOBallelesthathadamajorinfluenceonplasmalevelsofapoB100FamilialhypocholesterolemiacanbecausednotonlybydefectsintheLDLreceptor(LDLR606945)butalsobymutationsinapolipoproteinBcausingdecreasedLDLRbindingaffinitysocalledfamilialliganddefectiveapolipoproteinBThefirstmutationofthissortwasdescribedbySoriaetal(1989)see1077300009AsecondwasdescribedbyPullingeretal(1995)see1077300017DataongenefrequenciesofallelicvariantsweretabulatedbyRoychoudhuryandNei(1988)Lintonetal(1993)tabulated25apoBgenemutationsassociatedwithfamilialhypobetalipoproteinemiaFamilialhypobetalipoproteinemia(FHBL)isanautosomaldominantdisorderoflipidmetabolismcharacterizedbyextremelylowplasmalevelsofapolipoproteinBaswellaslowlevelsoftotalandlowdensitylipoprotein(LDL)cholesterolPulaietal(1998)commentedthatvarioustruncatedformsofapoBhavebeenfoundtosegregatewiththeFHBLphenotypeinmorethan30kindredsTheyreportedstudiesof6kindredsinwhichnotruncatedformsofapoBproteinweredetectedwithsensitiveimmunoblottingintheplasmasofanyoftheaffectedindividualsPersonswithapoBlevelsinthefifthcentilefortheirageandsexwereconsideredasaffectedwithFHBLLinkageanalysiswith3microsatellitemarkersflankingtheAPOBgenea3primeVNTRmarkerandanintragenicmarkeryielded2pointlinkageofFHBLtothe3primeVNTRmarkerwithacombinedmaximumlodscoreof85attheta=00for5ofthe6familiesAtestofhomogeneitydifferentiatedthesixthfamilyfromtheother5ThesekindredsdemonstratedtheheterogeneityofFHBLandalsoofferedthepossibilitytoinvestigateasyetundescribedmutationsofAPOBresultinginalterationsofapoBmetabolismTheunlinkedkindredmayshedlightonanovelgenecontributingtothelowapoBphenotypeseeFHBL2(605019)Schonfeld(1998)statedthatinallreportedkindredsinwhichthe'hypobeta'traitcosegregatedwithanapoBtruncationheterozygotes(documentedbyeitherproteinorgenomicDNAanalysis)showedthetraitInfastingheterozygotesthereare2populationsofapoBcontaininglipoproteinsthosethatcontainthetruncationandthosethatcontainthenormalfulllengthapoB100ThelowcholesterollevelsareduetothelowlevelsofapoBcontaininglipoproteins(VLDLandparticularlyLDL)thattransportmostofthecholesterolinplasmaInturnlowlevelsofapoBareduetolowproductionratesofbothmutantandwildtypeformsofapoBinheterozygotesInsomecasesthereisalsoenhancedclearancefromplasmaLowproductionofatruncatedformisprobablyduetolowlevelsofthetruncationspecifyingmRNAItisnotclearwhywildtypeapoB100isproducedatlowerthanexpectedratesinheterozygotesKairamkondaandDalzell(2003)described3sibswithvitaminEdeficiencyandsymptomsofmalabsorptionwithdocumentedexcessivefecalfatexcretionandlowcholesterolapoBandvitaminElevelsAlthoughthepathogenesiswasnotestablishedtheauthorspostulatedthatthesibshadheterozygousFHBLduetoanovelmutationofapoBbecauseofpersistentposttherapeuticlowcholesterolandapoBlevelsANIMALMODELRapaczetal(1986)describedastrainofpigsbearing3immunogeneticallydefinedlipoproteinassociatedmarkers(allotypes)associatedwithmarkedhypercholesterolemiadespitealowfatcholesterolfreedietLDLreceptoractivitywasnormalBy7monthsofagetheanimalshadextensiveatheroscleroticlesionsinall3coronaryarteriesOneofthe3variantapolipoproteinswasapolipoproteinBTheidentityoftheother2apolipoproteinswasnotclearalthoughonewasacomponentoflowdensitylipoproteinandwasgeneticallylinkedtothevariantidentifiedwithapolipoproteinBHomanicsetal(1993)usedgenetargetingtogenerateamousemodelofhypobetalipoproteinemiaMicecarryingthedisruptedApobgenesynthesizedapoB48andatruncatedapoB(apoB70)butnoapoB100InadditiontohavingalipoproteinphenotyperemarkablysimilartofamilialhypobetalipoproteinemiainhumansthesemicealsoexhibitedexencephalusandhydrocephalusHuangetal(1995)likewisegeneratedAPOBgeneknockoutmicebytargetingthegeneinembryonicstemcellsHomozygousdeficiencyledtoembryoniclethalitywithresorptionofallembryosbygestationalday9HeterozygotesshowedanincreasedtendencytointrauterinedeathwithsomefetuseshavingincompleteneuraltubeclosureandsomelivebornheterozygotesdevelopinghydrocephalusMostheterozygousmalesweresterilealthoughtheGUsystemandspermweregrosslynormalViableheterozygoteshadnormaltriglyceridesbuttotalLDLandHDLcholesterollevelsweredecreasedby3737and39%respectivelyHepaticandintestinalAPOBmRNAlevelsweredecreasedinheterozygotesCallowetal(1995)notedthattheengineeringofmicethatexpressahumanAPOBtransgeneresultsinanimalswithhighlevelsofhumanlikeLDLparticlesAdditionallythroughcrosseswithtransgenicsforthehumanLPAgenehighlevelsofhumanlikelipoprotein(a)particlesareseenCallowetal(1995)foundthatsuchmicedemonstratedmarkedincreasesinapoBandLDLresultinginatheroscleroticlesionsextendingdowntheaortathatresembledhumanlesionsimmunochemicallyThefindingssuggestedtotheauthorsthatAPO(a)associatedwithapo(B)andlipidmayresultinamoreproatherogenicstatethanwhenAPO(a)isfreeinplasmaHuangetal(1996)foundthatmalemiceheterozygousfortargetedmutationoftheApoBgeneexhibitseverelycompromisedfertilitySpermfromthesemicefailtofertilizeeggsbothinvitroandinvivoHoweverthesespermwereabletofertilizeeggsoncethezonapellucidawasremovedbutdisplayedpersistentabnormalbindingtotheeggafterfertilizationInvitrofertilizationrelatedandotherexperimentsrevealedreducedspermmotilitysurvivaltimeandspermcountalsocontributedtotheinfertilityphenotypeRecognitionoftheinfertilityphenotypeledtotheidentificationofApoBmRNAinthetestesandepididymidesofnormalmiceandthesetranscriptsweresubstantiallyreducedinthemutantanimalMoreoverwhenthegenomicsequenceencodinghumanApoBwasintroducedintotheseanimalsnormalfertilitywasrestoredThefindingsofHuangetal(1996)suggestedthattheAPOBlocusmayhaveanimportantimpactonmalefertilityandidentifiedapreviouslyunrecognizedfunctionofApoBToprovidemodelsforunderstandingthephysiologicpurposeforthe2formsofapoB(B100andB48)Fareseetal(1996)usedtargetedmutagenesisoftheAPOBgenetogeneratemicethatsynthesizedapoB48exclusivelyandmicethatsynthesizedapoB100exclusivelyTheB48onlyandB100onlymicewereproducedbyintroducingintomouseEScellsstopandnonstopmutationsrespectivelyintheapoB48editingcodon(codon2153)ofthemouseApobgeneBothtypesofmicedevelopednormallywerehealthyandwerefertileThusapoB48synthesissufficedfornormalembryonicdevelopmentandthesynthesisofapoB100intheintestineadultmicecausednoreadilyapparentadverseeffectsonintestinalfunctionornutritionComparedwithwildtypemicefedthesamedietthelevelsofLDLcholesterolandVLDLandLPLtriacylglycerolswerelowerintheB48onlymiceandhigherintheB100onlymiceFareseetal(1996)statedthatinthesettingofapoEdeficiencytheB100onlymutationloweredcholesterollevelsconsistentwiththefactthatB100lipoproteinscanbeclearedfromtheplasmaviatheLDLreceptorwhereasB48lipoproteinslackingapoEcannotBorenetal(1998)expressedmutantformsofhumanapoBintransgenicmicepurifiedtheresultinghumanrecombinantLDLandtestedfortheirreceptorbindingactivityTheyshowedthataminoacids3359to3369bindtotheLDLreceptorandthatarginine3500isnotdirectlyinvolvedinreceptorbindingHowevertheCterminal20%ofapoB100isnecessaryfortheR3500QmutationtodisruptreceptorbindingsinceremovaloftheCterminusinfamilialdefectiveapoB100(FDB)LDLresultedinnormalreceptorbindingactivitySimilarlyremovaloftheCterminusofapoB100onreceptorinactiveVLDLdramaticallyincreasedapoBmediatedreceptorbindingactivityBorenetal(1998)proposedthattheCterminusnormallyfunctionstoinhibittheinteractionofapoB100VLDLwiththeLDLreceptorbutaftertheconversionoftriglyceriderichVLDLtosmallercholesterolrichLDLarginine3500interactswiththeCterminuspermittingnormalinteractionbetweenLDLanditsreceptorMoreoverthelossofarginineatthissitedestabilizesthisinteractionresultinginreceptorbindingdefectiveLDLSkalenetal(2002)createdtransgenicmiceexpressing5typesofhumanrecombinantLDLfedthemanatherogenicdietfor20weeksandquantitatedtheextentofatherosclerosisTheyusedthesemodelstotestthehypothesisthatthesubendothelialretentionofatherogenicapoBcontaininglipoproteinsistheinitiatingeventinatherogenesisTheextracellularmatrixofthesubendotheliumparticularlyproteoglycansisthoughttoplayamajorroleintheretentionofatherogeniclipoproteinsTheinteractionbetweenatherogeniclipoproteinsandproteoglycansinvolvesanionicinteractionbetweenbasicaminoacidsinapoB100andnegativelychargedsulfategroupsontheproteoglycansSkalenetal(2002)presenteddirectexperimentalevidencethattheatherogenicityofapoBcontaininglowdensitylipoproteinsislinkedtotheiraffinityforarterywallproteoglycansMiceexpressingproteoglycanbindingdefectiveLDLdevelopedsignificantlylessatherosclerosisthanmiceexpressingwildtypecontrolLDLSkalenetal(2002)concludedthatsubendothelialretentionofapoB100containinglipoproteinisanearlystepinatherogenesisEspinosaHeidmannetal(2004)studiedthedevelopmentofbasallaminardepositsintheeyesoftransgenicmicethatoverexpressedapoB100ThemicewerefedahighfatdietandtheireyeswereexposedtobluegreenlightTheresultssuggestedthatageandhighfatdietpredisposedtotheformationofbasallaminardepositsbyalteringhepaticand/orretinalpigmentepitheliallipidmetabolisminwaysmorecomplicatedthanplasmahyperlipidemiaaloneVitaminEtreatedmiceshowedminimalformationofbasallaminardeposits(selectedexamples)0001HYPOBETALIPOPROTEINEMIAFAMILIAL[APOBASN1728THRANDSER1729TER]Inapatientwithhypobetalipoproteinemiaandsmallamountsoftruncatedprotein(B37)inVLDLLDLandHDLfractionsoftheplasmaYoungetal(19871988)founddeletionofnucleotides53915394resultinginaframeshiftcausingchangeofasn1728tothrandser1729tostopThetruncatedapoBproteincontained1728aminoacidsThiswasoneofthemutantallelesinthefamilywithhypobetalipoproteinemiafirstreportedbySteinbergetal(1979)Lintonetal(1992)investigatedthereasonforthecuriousfindingthatlowlevelsofapoB100wereproducedbythemutantallelecarryingthismutationThecluethatledtotheunderstandingofwhatwasgoingonwiththisallelewastherecognitionthattheprobandinthefamilyHJBaswellastheother2compoundheterozygotesactuallyhad4bonafideapoBspecieswithintheirplasmalipoproteinsapoB37apoB48apoB100andapoB86Lintonetal(1992)demonstratedthattheapoB86andapoB100wereproductsofasinglemutantapoBallelewhichtheydesignatedtheapoB86alleleTheyshowedthatthisallelehasa1bpdeletioninexon26oftheAPOBgeneandthatthisframeshiftisresponsibleforthesynthesisofapoB86NeverthelessasshownbycellcultureexpressionstudiestheapoB86allelewhichcontainsaprematurestopcodonresultsinthesynthesisofafulllengthapoBproteinThe1bpdeletioncreatesastretchof8consecutiveadeninesAdditionofasingleadeninewithinthe8consecutiveadeninesappearstotakeplaceduringtranscriptionrestoringthecorrectreadingframeandaccountingfortheformationofapoB100bytheapoB86alleleElevenpercentofthecDNAcloneshadanadditionaladeninewithinthestretchof8adenines0002HYPOBETALIPOPROTEINEMIAFAMILIALASSOCIATEDWITHAPOB39[APOB1BPDELFS1799TER]APOB39Collinsetal(1988)describedatruncatedapoBproteinduetodeletionofasingleguaninenucleotidefromleucinecodon1794resultinginaframeshiftandastopcodonaftercodon1799ThetruncatedproteinwasreferredtoasapoB39ThemutationoccurredinaCpGdinucleotide0003HYPOBETALIPOPROTEINEMIAFAMILIAL[APOBARG1306TER]AsecondtruncatedvariantofapoBfoundinhypobetalipoproteinemiabyCollinsetal(1988)hadachangeofargininecodon1306convertingittoastopcodonandresultinginaproteinof1305residueswhichhowevercouldnotbedetectedinthecirculationThismutationwasaCtoTtransitioninaCpGdinucleotide0004HYPOBETALIPOPROTEINEMIAFAMILIALASSOCIATEDWITHAPOB40[APOBVAL1829CYS]APOB40Kruletal(1989)found2distincttruncatedapoBproteinsapoB40andapoB90inakindredwithhypobetalipoproteinemiaTalmudetal(1989)showedthatthemolecularbasiswasdeletionof2nucleotidesconvertingval1829tocysandcodon1830tostop0005HYPOBETALIPOPROTEINEMIAFAMILIALASSOCIATEDWITHAPOB90ORAPOB89[APOBGLU4034ARG]APOB90/APOB89SeeKruletal(1989)Themolecularbasiswasdeletionof1nucleotideinglutamicacidcodon4034convertingthatcodontoarginineandcausingaframeshiftwithastopcodonatposition4040(Talmudetal1989)Parhoferetal(1992)showedthatenhancedcatabolismofVLDLIDLandLDLparticlescontainingthetruncatedapolipoproteinisresponsiblefortherelativelylowlevelsofapoB89seeninthesesubjects0006HYPOBETALIPOPROTEINEMIAFAMILIALASSOCIATEDWITHAPOB46[APOBARG2058TER]APOB46Youngetal(1989)characterizedanapoBgenemutationinakindredwithfamilialhypobetalipoproteinemiaSixmembersofthefamilyhadlowplasmaapoBandLDLcholesterollevelsandeachwasshowntobeheterozygousforamutantapoBallelethatyieldedauniquetruncatedspeciesofapoBnamelyapoB46withonly2037aminoacidsTheyfurthershowedthatapoB46iscausedbythesubstitutionofTforCatapoBcDNAnucleotide6381resultinginanonsensemutationThechangeoccurredinaCGdinucleotideACtoTtransitionintheAPOBgenewasresponsibleforhypobetalipoproteinemiainoneofthefamiliesstudiedbyCollinsetal(1988)LikeCETPdeficiency(607322)thisappearstobeanantiatherogenicmutation0007HYPOBETALIPOPROTEINEMIAFAMILIALASSOCIATEDWITHAPOB87[APOB]APOB87Youngetal(1990)referredtoatruncatedapoBspeciesapoB87onthebasisoftheirunpublishedwork0008HYPOBETALIPOPROTEINEMIAFAMILIALASSOCIATEDWITHAPOB31[APOB1BPDEL1425G]APOB31Youngetal(1990)identifiedamutationoftheAPOBgenethatresultedinformationofatruncatedapoBspeciesapoB31Themutationconsistedofdeletionofasingleguanineresiduewhichcausedaframeshiftandaprematureterminationwithformationofaproteinpredictedtocontain1425aminoacidsThisistheshortestofthemutantapoBspeciesidentifiedintheplasmaofsubjectswithhypobetalipoproteinemiaIncontrasttothelongertruncatedproteinsapoB31wasundetectableinVLDLandLDLbutwaspresentintheHDLfractionandinthelipoproteindeficientfractionoftheplasmaThismutationwasfoundinthecourseofstudyingtheapoB46mutant(Youngetal1989)0009HYPERCHOLESTEROLEMIADUETOLIGANDDEFECTIVEAPOLIPOPROTEINB100[APOBARG3500GLN]VegaandGrundy(1986)showedthatsomepatientswithhypercholesterolemia(143890)havereducedclearanceofLDLnotbecauseofdecreasedactivityofLDLreceptorsbutbecauseofadefectinthestructure(orcomposition)ofLDLthatreducesitsaffinityforreceptorsIn5of15patientsturnoverratesindicatedthatclearanceofautologousLDLwassignificantlylowerthanforhomologousnormalLDLInthese5patientsautologousLDLappearedtobeapoorligandforLDLreceptorsTheauthorsdidnotcarrytheinvestigationsfarenoughtodeterminewhetherabnormalityintheprimarystructureofapoB100accountedforthepoorbindingtoreceptorsInnerarityetal(1987)foundthatmoderatehypercholesterolemiacouldbeattributedtodefectivereceptorbindingofageneticallyalteredapoB100totheLDLreceptorAfindingofthesameabnormalityinseveraloftheproband'sfirstdegreerelativesindicatedtheinheritednatureofthedefectTheprobandofthefamilystudiedbyInnerarityetal(1987)wasdescribedearlierbyVegaandGrundy(1986)ThisdisorderwasreferredtoasfamilialdefectiveapolipoproteinB100(144010)Weisgraberetal(1988)foundanantibodywhoseisotopeisbetweenresidues3350and3506ofapoBthatdistinguishesabnormalLDLfromnormalLDLinthisdisordertheantibodyMB47boundwithahigheraffinitytoabnormalLDLThusanassaywasprovidedforscreeninglargepopulationsforthisdisorderIllingworthetal(1992)foundthatLDLcholesterolwasreducedafteradministrationoflovastatinin12hypercholesterolemicpatientsfrom10unrelatedfamilieswithfamilialdefectiveapoB100Byextensivesequenceanalysisofthe2allelesoftheAPOBgeneofasubjectheterozygousforfamilialdefectiveapolipoproteinSoriaetal(1989)demonstratedamutationinthecodonforaminoacid3500thatresultsinthesubstitutionofglutamineforarginineThissamemutantallelewasfoundin6otherunrelatedsubjectsandin8affectedrelativesin2ofthesefamiliesApartialhaplotypeofthismutantapoB100allelewasconstructedbysequenceanalysisandrestrictionenzymedigestionatpositionswherevariationsintheapoB100areknowntooccurThishaplotypewasfoundtobethesamein3probandsand4affectedmembersof1familyandlacksapolymorphicXbaIsitewhosepresencehasbeencorrelatedwithhighcholesterollevelsThusitappearsthatthemutationinthecodonforaminoacid3500(CGGtoCAG)aCGmutationhotspotdefinesaminorapoB100alleleassociatedwithdefectivelowdensitylipoproteinsandhypercholesterolemiaLudwigandMcCarthy(1990)used10markersforhaplotypingattheAPOBlocusincasesoffamilialdefectiveapolipoproteinB1008diallelicmarkerswithinthestructuralgeneand2hypervariablemarkersflankingthegeneIn14unrelatedsubjectsheterozygousforthemutation7of8unequivocallydeducedhaplotypeswereidenticaland1revealedonlyaminordifferenceatoneofthehypervariablelociThegenotypesoftheother6affectedsubjectswasconsistentwiththesamehaplotypeFamilialdefectiveapolipoproteinB100(FDB)resultsfromaGtoAtransitionatnucleotide10708inexon26oftheAPOBgeneLudwigandMcCarthy(1990)interpretedthedataasconsistentwiththeexistenceofacommonancestralchromosomeInascreeningfortheAPOB3500mutationbyPCRamplificationandhybridizationwithanallelespecificoligonucleotideLouxetal(1993)foundonly1caseamong101FrenchsubjectswithfamilialhypercholesterolemiaThesonofthisindividuala45yearoldmanwasfoundalsotohavethemutationHaplotypeanalysisrevealedstrictidentitytothatpreviouslyreportedbyLudwigandMcCarthy(1990)thussupportingauniqueEuropeanancestryThefamilylivedinthesouthwestofFranceandhadnoknowledgeofGermanicoriginRauhetal(1992)statedthatthefrequencyofthearg3500toglnmutationhasbeenfoundtobeapproximately1/500to1/700inseveralCaucasianpopulationsinNorthAmericaandEuropeOntheotherhandFriedlanderetal(1993)foundnoinstanceofthismutationinalargescreeningprograminIsraelTheypointedoutthatthemutationhasalsonotbeenfoundinFinland(Hamalainenetal1990)andissaidtobeabsentinJapanTybjaergHansenandHumphries(1992)gaveareviewsuggestingthattheriskofprematurecoronaryarterydiseaseinthecarriersofthemutationisincreasedtolevelsashighasthoseseeninpatientswithfamilialhypercholesterolemiaatage50about40%ofmalesand20%offemalesheterozygousforthemutationhavedevelopedcoronaryarterydiseaseMarzetal(1992)foundonlymoderatehypercholesterolemiaina54yearoldmanwhowashomozygousforthearg3500toglnmutationandonanormaldietwithoutlipidloweringmedicationTherewasnoevidenceofatherosclerosisandnohistoryofcardiovascularcomplaintsThelevelsofapoEcontaininglipoproteinswerenormalMarzetal(1992)suggestedthattheintactmetabolismofapoEcontainingparticlesdecreasesLDLproductioninthisdisorderexplainingthedifferencefromfamilialhypercholesterolemiaduetoareceptordefectinwhichapoElevelsareraisedMarzetal(1993)investigatedpossiblecompensatorymechanismsthatmayhavealleviatedtheconsequencesofthefamilialdefectiveapoB100(FDB)TheyshowedthatthereceptorinteractionofbuoyantLDLisnormalduetothepresenceofapoEintheseparticlesInadditiontheyprovidedevidencethatthearg3500toglnsubstitutionprofoundlyalterstheconformationoftheapoBreceptorbindingdomainwhenapolipoproteinBresidesonparticlesatthelowerandupperlimitsoftheLDLdensityrangeTheyconcludedthatthesemechanismsdistinguishFDBfromFHandaccountforthemildhypercholesterolemiainhomozygousFDBAmong43patientswithclinicallyandbiochemicallydefinedtypeIIIhyperlipoproteinemia(107741)FeussnerandSchuster(1992)foundnoinstanceofthearg3500toglnmutationInthecourseofinvestigatingthereasonthat2unrelatedFrenchpatientsheterozygousformutationsintheLDLRgenehadaggravatedhypercholesterolemiaBenlianetal(1996)foundthateachcarriedtheidenticalarg3500toglnmutationintheAPOBgeneieweredoubleheterozygotesOneofthepatientswasa10yearoldboywhenhewasreferredforhypercholesterolemiadiscoveredatthetimeofacardiacarrestHehadnoplanarxanthomataalthoughheexhibitedbilateralxanthomasoftheAchillesandmetacarpalphalangealtendonsPeripheralarterialdiseasewasdemonstratedbythepresenceofarterialmurmursandbyarterialwallirregularityonultrasoundanalysisStenosesofcoronaryarteriesnecessitatedsurgicalangioplastyThesecondpatientwasa39yearoldmanwithmyocardialinfarctionandacuteischemiaofthelegsBothfamiliescamefromthePercheregionfromwhichmanyFrenchCanadiansoriginatedTheLDLRmutationstrp66togly(6069450003)andglu207tolys(6069450007)hadbeenpreviouslydescribedinFrenchCanadiansRubinszteinetal(1993)describedanAfrikanerfamilywith6FH/FDBdoubleheterozygotescarryinganotherLDLRmutationasp206toglu(6069450006)(Benlianetal(1996)inthetitleoftheirarticlecorrectlyreferredtothesepatientsasdoubleheterozygotesinthepaperitselftheyincorrectlyreferredtothemasFH/FDBcompoundheterozygotesThelattertermisusedforheterozygosityforallelesatthesamelocus)InapatienthomozygousfortheR3500QmutationSchaeferetal(1997)foundLDLcholesterolandapoBconcentrationsapproximatelytwicenormalwhereasapoEplasmalevelwaslowUsingastableisotopelabelingtechniquetheyobtaineddatashowingthattheinvivometabolismofapoB100containinglipoproteinsinFDBisdifferentfromthatinfamilialhypercholesterolemiainwhichLDLreceptorsaredefectiveAlthoughtheresidencetimesofLDLapoB100appearedtobeincreasedtoapproximatelythesamedegreeLDLapoB100syntheticratewasincreasedinFHanddecreasedinFDBThedecreasedproductionofLDLapoB100inFDBmayoriginatefromenhancedremovalofapoEcontainingLDLprecursorsbyLDLreceptorswhichmaybeupregulatedinresponsetothedecreasedfluxofLDLderivedcholesterolintohepatocytesAlmostallindividualswithfamilialdefectiveapoB100areofEuropeandescentandinalmostallcasesthemutationisonachromosomewithararehaplotypeattheapoBlocussuggestingthatallprobandsaredescendedfromacommonancestorinwhomtheoriginalmutationoccurredDistributionofthemutationisconsistentwithanorigininEurope6000to7000yearsagoMyantetal(1997)estimatedtheamountofrecombinationbetweentheAPOBgeneandmarkersonchromosome2in34FDB(R3500Q)probandsinwhomthemutationisontheusual194haplotypeSignificantlinkagedisequilibriumwasfoundbetweentheAPOBgeneandmarkerD2S220Theyidentified3YACsthatcontainedtheAPOBgeneandD2S220Theshortestrestrictionfragmentcommontothe3YACsthatcontainbothlociwas240kblongNoshorterfragmentswithbothlociwereidentifiedOntheassumptionthat1000kbcorrespondsto1cMMyantetal(1997)deducedthattherecombinationdistancebetweenD2S220andtheAPOBgeneisabout024cMCombiningthisvaluewiththelinkagedisequilibriumobservedbetweenthe2lociintheprobandstheyestimatedthattheancestralmutationoccurredabout270generationsagoTheypostulatedthattheoriginalmutationoccurredinthecommonancestoroflivingFDB(R3500Q)probandswholivedinEuropeabout6750yearsagoTybjaergHansenetal(1998)foundthattheR3500QmutationintheAPOBgeneispresentinapproximately1in1000personsinDenmarkandcausesseverehypercholesterolemiaandincreasestheriskofischemicheartdiseaseHeterozygouscarriersofthearg3531tocys(1077300017)mutationwhichispresentinthepopulationinapproximatelythesamefrequencyandalsoisassociatedwithfamilialdefectiveapolipoproteinB100wasnotassociatedwithhigherthannormalplasmacholesterollevelsoranincreasedriskofischemicheartdiseaseSaintJoreetal(2000)estimatedtherespectivecontributionsoftheLDLRgenedefectAPOBgenedefectandothergenedefectsinautosomaldominanttypeIIahypercholesterolemiabystudying33wellcharacterizedFrenchfamiliesinwhichthisdisorderhadbeendiagnosedoveratleast3generationsUsingthecandidategeneapproachtheyfoundthatdefectsintheLDLRgeneaccountedforthedisorderinabout50%ofthefamiliesTheestimatedcontributionofanAPOBgenedefectwasonly15%ThislowestimationofinvolvementoftheAPOBgenedefectwasstrengthenedbytheexistenceofonly2probandscarryingtheR3500QmutationSurprisingly35%ofthefamilieswereestimatedtobelinkedtoneitherLDLRnorAPOBTheresultssuggestedthatgeneticheterogeneityintypeIIahypercholesterolemiahadbeenunderestimatedandthatatleast3majorgroupsofdefectswereinvolvedTheauthorswereunabletoestimatethecontributionoftheFH3gene(603776)Borenetal(2001)concludedthatnormalreceptorbindingofLDLinvolvesaninteractionbetweenarginine3500andtryptophan4369inthecarboxyltailofapoB100Trp4369totyr(W4369Y)LDLandarg3500togln(R3500Q)LDLisolatedfromtransgenicmicehadidenticallydefectiveLDLbindingandahigheraffinityforamonoclonalantibodythathasanepitopeflankingresidue3500Borenetal(2001)concludedthatarginine3500interactswithtryptophan4369andfacilitatestheconformationofapoB100requiredfornormalreceptorbindingofLDLTheydevelopedamodelthatexplainedhowthecarboxylterminusofapoB100interactswiththebackboneofapoB100thatenwrapstheLDLparticleThemodelexplainedhowallknownliganddefectivemutationsinapoB100includinganewlydiscoveredR3480WmutationcausedefectivereceptorbindingHorvathetal(2001)studied130unrelatedindividualswithhypercholesterolemiainBulgariaFouroftheseindividualswerefoundtobecarriersofthismutationHorvathetal(2001)concludedthatthismutationaccountsfor099to817%(95%CI)ofcasesofhypercholesterolemiainBulgariaandthereforerepresentsthemostcommonsinglemutationassociatedwiththisconditioninBulgariaBednarskaMakaruketal(2001)foundthearg3500toglnmutationin25%(13/525)ofunrelatedpatientswithhypercholesterolemiainPolandAllthepatientsbelongedtothetypeIIAhyperlipoproteinemiagroupIn65patientswiththeclinicalcharacteristicsoffamilialhypercholesterolemiathefrequencyofthearg3500toglnmutationwas108%(7/65)ThesamehaplotypeattheAPOBlocusinthecarriersofthismutationinPolandasinotherpopulationsfromwesternEuropesuggesteditscommonorigin0010HYPOBETALIPOPROTEINEMIAFAMILIAL[APOBEX21DEL]InanArabpatientwithhypobetalipoproteinemiaandabsentplasmaapolipoproteinBHuangetal(1989)demonstrateddeletionoftheentireexon21(211basepairscodingforaminoacids1014to1084)0011APOBPOLYMORPHISMINSIGNALPEPTIDE[APOBINSANDDEL]Visvikisetal(1990)describedaninsertion/deletionpolymorphisminthesignalpeptideOneallelecodingapeptide27aminoacidslonghadafrequencyof0655thesecondallelecodingapeptide24aminoacidslonghadafrequencyof03450012HYPOBETALIPOPROTEINEMIAFAMILIAL[APOBLEU3041TER]Inamanwithhypobetalipoproteinemiaand6ofhis12childrenWeltyetal(1991)foundthattheplasmalipoproteinscontainedauniquespeciesofapolipoproteinBapoB67inadditiontothenormalspeciesapoB100andapoB48FurtherstudyindicatedthattheapoB67wasatruncatedspeciesthatcontainedapproximatelytheaminoterminal3000to3100aminoacidsofapoB100HeterozygositywasidentifiedforamutantAPOBallelecontainingasinglenucleotidedeletioninexon26(cDNAnucleotide9327)Thechangeincodon3041fromATA(leu)toTAG(stop)ledtotruncationafteraminoacid3040MeantotalandLDLcholesterollevelswere120and42mg/dlrespectivelyAllaffectedmembersofthekindredhadhighHDLcholesterollevels0013HYPOBETALIPOPROTEINEMIANORMOTRIGLYCERIDEMIC[APOBGLN2252TER]Malloyetal(1981)describedapatient(AF)withametabolicdisordertheytermednormotriglyceridemicabetalipoproteinemiaSimilarcaseswerereportedbyTakashimaetal(1985)Herbertetal(1985)andHaranoetal(1989)ThedisorderwascharacterizedbytheabsenceofLDLsandapoB100inplasmawithapparentlynormalsecretionoftriglyceriderichlipoproteinscontainingapoB48SubsequentstudiesinAFsuggestedthatthepatient'splasmamightbeatruncatedformofapoB100slightlylongerthanthenormalapoB48chainHardmanetal(1991)demonstratedthatthepatientwashomozygousforasingleCtoTsubstitutionatnucleotide6963ofapoBcDNAThissubstitutionresultedinachangefromCAG(glutamine)toTAG(stop)atposition2252ThusthiswasarareexampleofhomozygoushypobetalipoproteinemiaBecauseLDLparticlesthatcontainedapoB50lackedtheputativeliganddomainoftheLDLreceptortheverylowlevelofLDLwaspresumablyduetotherapidremovaloftheabnormalVLDLparticlesbeforetheirconversiontoLDLcouldtakeplaceAsreviewedbyHardmanetal(1991)aconsiderablenumberofmutationsresultingintruncatedversionsofapoBhavebeendescribedthesmallestvariantbeingapoB31andthelongestapoB90Using3geneticmarkersoftheAPOBgeneinastudyofthefamilyreportedbyTakashimaetal(1985)Naganawaetal(1992)foundthattheprobandandheraffectedbrothershowedcompletelydifferentAPOBallelesindicatingthatinthisfamilythedefectwasnotintheAPOBgeneHomeretal(2005)suggestedthattheterm'normotriglyceridemichypobetalipoproteinemia'ispreferredto'normotriglyceridemicabetalipoproteinemia'becauseabetalipoproteinemia(ABL200100)referstothedisordercausedbymutationintheMTPgene(157147)0014HYPOBETALIPOPROTEINEMIAFAMILIALASSOCIATEDWITHAPOB32[APOBGLN1450TER]APOB32InapersonwithheterozygoushypobetalipoproteinemiaMcCormicketal(1992)identifiedanonsensemutationgln1450toterthatpreventedfulllengthtranslationThenewapolipoproteinBapoB32ispredictedtocontainthe1449aminoterminalaminoacidsofapoB100Itwasassociatedwithamarkedlydecreasedleveloflowdensitylipoprotein(LDLcholesterol)UniqueamongthetruncatedapoBspeciesapoB32wasfoundinthehighdensitylipoproteinandlipoproteindepletedfractionssuggestingthatitwasmainlyassembledintoabnormallydenselipoproteinparticles0015HYPOBETALIPOPROTEINEMIAFAMILIAL[APOBARG2495TER]Talmudetal(1992)identifiedaCtoTtransitionatnucleotide7692oftheAPOBgenewhichchangedtheCGAargininecodontoastopcodonresultinginaprematureterminationofapoB100Thetruncatedproteinwaspredictedtobe2494aminoacidslongwiththepredictedsizeofapoB55ThepatienthadlowtotalcholesterolandLDLcholesterolasdidalsootherrelativesinanautosomaldominantpatternInadditionthepropositushismotherandbothofhissibshadatypicalretinitispigmentosaSincetheRPaffectedbrotherdidnothavetheAPOBmutationTalmudetal(1992)concludedthattheeyediseasewasindependentofthehypobetalipoproteinemiaTheyspeculatedhoweverthatareductioninapoBcontaininglipoproteinsmightalterthebalanceofthefattyacidsupplytotheretinaandthusaffecttheevolutionofretinitispigmentosainthisfamilyTheretinitispigmentosawaslateinonset0016HYPOBETALIPOPROTEINEMIAFAMILIAL[APOB1BPDEL]InHJBand2sibswithasymptomaticfamilialhypobetalipoproteinemiareportedbySteinbergetal(1979)Lintonetal(1992)demonstratedthatoneofthealleleswhichyieldedverylowlevelsofapoB100hadadeletionofasinglecytosineinexon26(nucleotide11840oftheapoBcDNA)Thisframeshiftmutationwaspredictedtoyielda20aminoacidsequence(KKQIMLKQSWIPHAAQPYSS)notfoundinthewildtypefollowedbyaprematurestopcodonIndeedtheyfoundanantiserumtoasyntheticpeptidecontainingthis20aminoacidsequence(frameshiftpeptide38773896)boundspecificallytoapoB86butnottoapoB100Thusthecompoundheterozygoteshad2mutantapoBallelesoneprimarilyresponsibleforapoB37(1077300001)andtheotherresponsibleforapoB86bothofwhichcontainedframeshiftmutationsinexon26Lintonetal(1992)furtherdemonstratedthatthe1bpdeletionintheapoB86allelecreatedastretchof8consecutiveadeninesAdditionofasingleadeninewithinthe8consecutiveadenineswouldbepredictedtocorrectthealteredreadingframetherebyresultingintheproductionofafulllengthproteinTheypresentedevidencethatasignificantpercentage(about11%)oftheapoBcDNAclonesfromrathepatomacellstransformedwithanapoBconstructcontainingthe1bpdeletionindeedhad9consecutiveadeninesItappearedthattheadditionofanextraadenineduringtranscriptionrestoredthecorrectreadingframeandaccountedfortheformationofsomeapoB100fromtheapoB86alleleOtherexperimentswerethoughttoexcludeanalternativeexplanationtheactivationofacrypticsplicesitewithinexon26upstreamfromthedeletion0017HYPERCHOLESTEROLEMIADUETOLIGANDDEFECTIVEAPOLIPOPROTEINB[APOBARG3531CYS]SuspectingthatmutationsintheAPOBgeneotherthanthearg3500toglnmutation(1077300009)maycausefamilialhypercholesterolemia(144010)Pullingeretal(1995)usedsinglestrandconformationpolymorphismanalysistoscreengenomicDNAfrompatientsattendingalipidclinicandlookedformutationsintheputativeLDLreceptorbindingdomainofapoB100Theyfoundanovelarg3531tocysmutationcausedbyaCtoTtransitionatnucleotide10800ina46yearoldwomanofCelticandNativeAmericanancestrywithprimaryhypercholesterolemiaandpronouncedperipheralvasculardiseaseAfterscreening1560individualsoneunrelated59yearoldmanofItalianancestrywasfoundtohavethesamemutationHehadcoronaryheartdiseaseatriglyceridecholesterolof310mg/dlandanLDLcholesterolof212mg/dlAtotalof8individualswerefoundwiththesamedefectinthefamiliesofthese2patientsTheageandsexadjustedTCandLDLCwere240and169respectivelyforthe8affectedindividualsascomparedwith185and124respectivelyfor8unaffectedfamilymembersInaduallabeledfibroblastbindingassayLDLfromthe8subjectswiththemutationhadanaffinityfortheLDLreceptorthatwas63%thatofcontrolLDLLDLfrom8unaffectedfamilymembershadanaffinityof91%BywayofcomparisonLDLfrom6patientsheterozygousforthearg3500toglnmutationhadanaffinityof36%Deducedhaplotypesusing10APOBgenemarkersshowedthearg3531tocysallelestobedifferentinthe2kindredsandindicatedthatthemutationsaroseindependentlyThiswasthesecondreportedcauseoffamilialliganddefectiveapoB0018HYPOBETALIPOPROTEINEMIAFAMILIAL[APOBIVS7AG2]HegeleandMiskie(2002)describedacanthocytosisina31yearoldwomanwithhomozygousfamilialhypobetalipoproteinemiaduetoasplicingmutationintheAPOBgeneIVS7AS2AGTreatmentwithfatsolublevitaminswasassociatedwitharrestoftheusuallyprogressiveneurologiccomplicationsofthisconditionHoweveracanthocytosispersistedThediagnosisofhypobetalipoproteinemiawasmadeattheageof11onthebasisofacanthocytosisandtheabsenceofapoBcontaininglipoproteinsTheconsanguineousparentswereheterozygotes0019HYPOBETALIPOPROTEINEMIAFAMILIAL[APOB1BPDEL4432T]Yueetal(2002)describeda1bpdeletion4432delTinexon26oftheAPOBgeneproducingaframeshiftandaprematurestopcodonandresultinginatruncatedapoB309Althoughthistruncationwasonly10aminoacidsshorterthanthewelldocumentedapoB31(1077300008)whichisreadilydetectableinplasmaapoB309wasundetectableMosttruncationsshorterthanapoB30arenotdetectableinplasma0020HYPOBETALIPOPROTEINEMIANORMOTRIGLYCERIDEMIC[APOB4BPDELNT36491]InapatientwithnormotriglyceridemichypobetalipoproteinemiaobesityandmentalretardationHomeretal(2005)identifiedcompoundheterozygosityfor2mutationsintheAPOBgeneOnewasa4bpdeletionbeginningatnucleotide36491inexon26predictedtoresultinaframeshiftandincorporationof5newaminoacidsbeforeencounteringaprematureterminationcodonatposition3053Thistranslatedproteinwouldbe66%offulllengthapoBwhichwouldallowforexpressionintheliverandforproductionofminuteamountsofVLDLandLDLAccordinglythepatientdidnothavefailuretothriveorsteatorrheaThesecondmutationwasa29142TAtransversioninexon23resultinginatyr1173toter(Y1173X1077300021)substitutionThetranslatedY1173Xproteinispredictedtobe258%ofapoB100andisnotexpressedinapoBcontaininglipoproteinsHomeretal(2005)suggestedthattheclinicalfeaturesofataxiavisualimpairmentandprobableneuropathyseeninthepatientresultedfromtheinabilitytotransporttheactivestereoisomerofvitaminEfromtheliverTheseclinicalfeaturesweresimilartothoseseeninisolatedvitaminEdeficiency(VED277460)Homeretal(2005)notedthattheclinicalfeaturesofthispatientweresimilartothoseofthepatientreportedbyMalloyetal(1981)(see1077300013)Homeretal(2005)suggestedthattheterm'normotriglyceridemichypobetalipoproteinemia'ispreferredto'normotriglyceridemicabetalipoproteinemia'becauseabetalipoproteinemia(ABL200100)referstothedisordercausedbymutationintheMTPgene(157147)0021HYPOBETALIPOPROTEINEMIANORMOTRIGLYCERIDEMIC[APOBTYR1173TER]See1077300020andHomeretal(2005)SEEALSOAggerbecketal(1974)AllisonandBlumberg(1965)Barnietal(1986)ButlerandBrunner(1969)Butleretal(1970)Carlssonetal(1985)Chanetal(1985)Cottrilletal(1974)Frossardetal(1986)Hegeleetal(1986)Illingworthetal(1979)Innerarityetal(1987)Knottetal(1986)Lawetal(1986)Morgantietal(1970)Protteretal(1986)Protteretal(1986)Shouldersetal(1985)Tamiretal(1976)Yangetal(1986)Youngetal(1987)Youngetal(1986)REFERENCES1AggerbeckLPMcMahonJPScanuAMHypobetalipoproteinemiaclinicalandbiochemicaldescriptionofanewkindredwithFriedreich'sataxiaNeurology24105110631974PubMedID44725442AllisonACBlumbergBSAnisoprecipitationreactiondistinguishinghumanserumproteintypesLancetI63463719613AllisonACBlumbergBSSerumlipoproteinallotypesinmanProgMedGenet41762011965PubMedID53191164AntonarakisSEPersonalCommunicationBaltimoreMd6/19875ArakiWHiroseSMimoriYNakamuraSKimuraJOhnoKShimadaTFamilialhypobetalipoproteinaemiacomplicatedbycerebellarataxiaandsteatocystomamultiplexJInternMed2291971991991PubMedID19976456BarniNTalmudPJCarlssonPAzoulayMDarnforsCHardingDWeilDGrzeschikKHBjursellGJunienCWilliamsonRHumphriesSETheisolationofgenomicrecombinantsforthehumanapolipoproteinBgeneandthemappingofthreecommonDNApolymorphismsofthegeneausefulmarkerforhumanchromosome2HumGenet733133191986PubMedID30178407BednarskaMakarukMBiskoMPulawskaMFHoffmanZacharskaDRodoMRoszczynkoMSolikTomassiABrodaGPolakowskaMPytlakAWehrHFamilialdefectiveapolipoproteinB100inagroupofhypercholesterolaemicpatientsinPolandidentificationofanewmutationThr3492IleintheapolipoproteinBgeneEuropJHumGenet98368422001PubMedID117817008BenlianPdeGennesJLDairouFHermelinBGinonIVillainELagardeJPFederspielMCBertrandVBernardCBereziatGPhenotypicexpressionindoubleheterozygotesforfamilialhypercholesterolemiaandfamilialdefectiveapolipoproteinB100HumMutat73403451996PubMedID87236849BergKBeckmanGBeckmanLAsearchforlinkagebetweentheAgand(dimeric)superoxidedismutase(SOD1)lociBirthDefectsOrigArtSerXI(3)67701975NoteAlternateCytogenetCellGenet14237240197510BergKHamesCDahlenGFrickMHKrishanIGeneticvariationinserumlowdensitylipoproteinsandlipidlevelsinmanProcNatAcadSci739379401976PubMedID17666211BergKPowellLMWallisSCPeaseRKnottTJScottJGeneticlinkagebetweentheantigenicgroup(Ag)variationandtheapolipoproteinBgeneassignmentoftheAglocusProcNatAcadSci83736773701986PubMedID287642412BergerGMBBrownGHendersonHEBonniciFApolipoproteinBdetectedintheplasmaofapatientwithhomozygoushypobetalipoproteinaemiaimplicationsforaetiologyJMedGenet201891951983PubMedID687610913BiemerJJMcCammonREThegeneticrelationshipofabetalipoproteinemiaandhypobetalipoproteinemiaareportoftheoccurrenceofbothdiseaseswithinthesamefamilyJLabClinMed855565651975PubMedID16451114BlumbergBSPersonalCommunicationPhiladelphiaPenn5/16/197815BlumbergBSAlterHJRiddellNMInheritedantigenicdifferencesinhumanserumbetalipoproteinsasecon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roteinBsynthesisbyhumanliverandintestineinvitroProcNatAcadSci83529653001986PubMedID346009145GlueckCJTsangRCMelliesMJFallatRWSteinerPMNeonatalfamilialhypobetalipoproteinemiaMetabolism256116141976PubMedID17897946HamalainenTPalotieAAaltoSetalaKKontulaKTikkanenMJAbsenceoffamilialdefectiveapolipoproteinB100inFinnishpatientswithelevatedserumcholesterolAtherosclerosis821771831990PubMedID237578247HaranoYKojimaHNakanoTHaradaMKashiwagiANakajimaYHidakaTHOhtsukiTSuzukiTTamuraAFujiiTNishimuraTOhtakaTShigetaYHomozygoushypobetalipoproteinemiawithsparedchylomicronformationMetabolism38171989PubMedID290982748HardmanDAProtterAAChenGCSchillingJWSatoKYLauKYamanakaMMikitaTMillerJCrispTMcEnroeGScarboroughRMKaneJPStructuralcomparisonsofhumanapolipoproteinsB48andB100Biochemistry26547854861987PubMedID367626549HardmanDAPullingerCRHamiltonRLKaneJPMalloyMJMolecularandmetabolicbasisforthemetabolicdisordernormotriglyceridemicabetalipoproteinemiaJClinInvest88172217291991PubMedID193965750HegeleRAHuangLSHerbertPNBlumCBBuringJEHennekensCHBreslowJLApolipoproteinBgenepolymorphismsassociatedwithmyocardialinfarctionNewEngJMed315150915151986PubMedID302400251HegeleRAMiskieBAAcanthocytosisinapatientwithhomozygousfamilialhypobetalipoproteinemiaduetoanovelAPOBsplicesitemutationClinGenet611011032002PubMedID1194008452HerbertPNHyamsJSBernierDNBermanMMSaritelliALLynchKMNicholsAVForteTMApolipoproteinB100deficiencyintestinalsteatosisdespiteapolipoproteinB48synthesisJClinInvest764034121985PubMedID403105753HiguchiKHospattankarAVLawSWMeglinNCortrightJBrewerHBJrHumanapolipoproteinB(apoB)mRNAidentificationoftwodistinctapoBmRNAsanmRNAwiththeapoB100sequenceandanapoBmRNAcontainingaprematureinframetranslationalstopcodoninbothliverandintestineProcNatAcadSci85177217761988PubMedID245034654HomanicsGESmithTJZhangSHLeeDYoungSGMaedaNTargetedmodificationoftheapolipoproteinBgeneresultsinhypobetalipoproteinemiaanddevelopmentalabnormalitiesinmiceProcNatAcadSci90238923931993PubMedID846014955HomerVMGeorgePMduToitSDavidsonJSWilsonCJMentalretardationandataxiaduetonormotriglyceridemichypobetalipoproteinemiaAnnNeurol581601632005PubMedID1598401656HorvathASavovAKirovSKarshelovaEPaskalevaIGoudevAGanevVHighfrequencyoftheApoB100R3500QmutationinBulgarianhypercholesterolaemicsubjectsJMedGenet385365402001PubMedID1149496557HospattankarAVFairwellTMengMRonanRBrewerHBJrIdentificationofsequencehomologybetweenhumanplasmaapolipoproteinB100andapolipoproteinB48JBiolChem261910291041986PubMedID352258558HuangLSMillerDABrunsGAPBreslowJLMappingofthehumanAPOBgenetochromosome2panddemonstrationofatwoallelerestrictionfragmentlengthpolymorphismProcNatAcadSci836446481986PubMedID300374359HuangLSRippsMEKormanSHDeckelbaumRJBreslowJLHypobetalipoproteinemiaduetoanapolipoproteinBgeneexon21deletionderivedbyAluAlurecombinationJBiolChem26411394114001989PubMedID256773660HuangLSVoyiaziakisEChenHLRubinEMGordonJWAnovelfunctionalroleforapolipoproteinBinmaleinfertilityinheterozygousapolipoproteinBknockoutmiceProcNatAcadSci9310903109071996PubMedID885528061HuangLSVoyiaziakisEMarkensonDFSokolKAHayekTBreslowJLapoBgeneknockoutinmiceresultsinembryoniclethalityinhomozygotesandneuraltubedefectsmaleinfertilityandreducedHDLcholesterolesterandapoA1transportratesinheterozygotesJClinInvest96215221611995PubMedID759360062IllingworthDRConnorWEBuistNRMJhaveriBMLinSSMcMurryMPSterolbalanceinabetalipoproteinemiastudiesinapatientwithhomozygousfamilialhypobetalipoproteinemiaMetabolism28115211601979PubMedID49197363IllingworthDRVakarFMahleyRWWeisgraberKHHypocholesterolaemiceffectsoflovastatininfamilialdefectiveapolipoproteinB100Lancet3395986001992PubMedID134710364InnerarityTLWeisgraberKHArnoldKSMahleyRWKraussRMVegaGLGrundySMFamilialdefectiveapolipoproteinB100lowdensitylipoproteinswithabnormalreceptorbindingProcNatAcadSci84691969231987PubMedID347781565InnerarityTLYoungSGPoksayKSMahleyRWSmithRSMilneRWMarcelYLWeisgraberKHStructuralrelationshipofhumanapolipoproteinB48toapolipoproteinB100JClinInvest80179417981987PubMedID368052866JacksonLFalkCTAllenFHJrBarrMApossiblegeneassignmenttochromosome21CytogenetCellGenet131001021974PubMedID436386467KahnJAGlueckCJFamilialhypobetalipoproteinemiaabsenceofatherosclerosisinapostmortemstudyJAMA24047481978PubMedID20790368KairamkondaVDalzellMUnusualpresentationofthreesiblingswithfamilialheterozygoushypobetalipoproteinaemiaEuropJPediat1621291312003PubMedID1265541369KeidarSEtzioniABrookJGGershoniBaruchRAviramMCompoundheterozygosityforabetalipoproteinaemiaandfamilialhypobetalipoproteinaemiaJMedGenet271331341990PubMedID231958270KnottTJPeaseRJPowellLMWallisSCRallSCJrInnerarityTLBlackhartBTaylorWHMarcelYMilneRJohnsonDFullerMLusisAJMcCarthyBJMahleyRWLevyWilsonBScottJCompleteproteinsequenceandidentificationofstructuraldomainsofhumanapolipoproteinBNature3237347381986PubMedID377399771KnottTJRallSCJrInnerarityTLJacobsonSFUrdeaMSLevyWilsonBPowellLMPeaseRJEddyRNakaiHByersMPriestleyLMRobertsonERallLBBetsholtzCShowsTBMahleyRWScottJHumanapolipoproteinBstructureofcarboxylterminaldomainssitesofgeneexpressionandchromosomallocalizationScie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