OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP1OMIMUniSTS0*608958GeneTestsLinksADENOSINEDEAMINASEADAAlternativetitlessymbolsADENOSINEAMINOHYDROLASEGenemaplocus20q1311TEXTDESCRIPTIONTheADAgeneencodesadenosinedeaminase(EC3544)anenzymethatcatalyzestheirreversibledeaminationofadenosineanddeoxyadenosineinthepurinecatabolicpathwaySeeADCP1(102710)andDPP4(102720)fordescriptionsofadenosinedeaminasecomplexingproteinsCLONINGWigintonetal(1983)isolatedpartialADAcDNAsequencesfromahumanTcelllymphoblastcDNAlibraryNorthernblotanalysisdetectedaminor58kbandamajor16kbmRNAtranscriptADAimmunoreactiveproteinandtranslatableADAmRNAwerefoundtobe6to8timeshigherinTlymphoblastlinesthaninBlymphoblastlineswhichcorrespondedtoincreasedADAcatalyticactivityandproteininTcellscomparedtoBcellsThedifferencesareduemainlytodifferencesintherateofdegradationoftheADAproteinValerioetal(1984)isolatedafulllengthADAcDNAencodinga363aminoacidproteinwithamolecularmassof40kDGENESTRUCTUREValerioetal(1985)determinedthattheADAgenespans32kbandcontains12exonsWigintonetal(1986)reportedthecompletesequenceandstructureofthehumanADAgeneKalmanetal(2004)statedthattheADAgenecontains10exonsMAPPINGBysomaticcellhybridizationCreaganetal(1973)andTischfieldetal(1974)mappedtheADAgenetochromosome20Valerioetal(1984)usedanADAcDNAprobeinSouthernhybridizationswithDNAfromahybridcellpaneltoassignthegenetochromosome20Mohandasetal(1984)reportedthatthegenesforADAandSAHHareonseparatepartsof20qseparatedby20q131Genedosagestudiesofadenosinedeaminaseandinosinetriphosphataseprovidedcorroborationofpartialtrisomy20diagnosedcytogenetically(Ruddetal1979)Nielsenetal(1986)studiedADAinacaseofpartialtrisomy20qresultingfromafamilialt(320)translocationGenedosagestudiesseemedtoexcludetheADAgenefromthedistalpartof20q(20q131qter)Bydosageeffectinapatientwithdeletionof20qPetersenetal(1987)assignedtheADAlocusto20q1311BymeansofinsituhybridizationtohighresolutionspreadsofsomaticandpachytenechromosomesJhanwaretal(1989)localizedtheADAgeneto20q12q1311MOLECULARGENETICSRothschildetal(1993)identifiedandmappednewdinucleotiderepeatpolymorphismsassociatedwiththeADAlocusSevereCombinedImmunodeficiencyduetoADADeficiencyIncelllinesfrom2patientswithseverecombinedimmunodeficiency(SCID)duetoADAdeficiency(102700)AdrianandHutton(1983)andWigintonetal(1983)found3to4foldincreasedlevelsofnormaltranslatableADAmRNAcomparedtonormalcontrolsTheauthorssuggestedthatthecellularADAdeficiencywassecondarytorapiddegradationofadefectiveADAproteinSimilarresultswerefoundbyAdrianetal(1984)InpatientswithSCIDduetoADAdeficiencyAkesonetal(1987)identifiedseveralmutationsintheADAgene(seeeg608958000460895800066089580017)Tzalletal(1989)identifiedand/orcharacterizedatleast9RFLPsattheADAlocusandstudiedthesein17patientswithcompleteADAdeficiencyandin10patientswithpartialADAdeficiencyGeneticcompoundsandhomozygoushaplotypeswereidentifiedamongbothtypesofpatientsDelayedorLateOnsetIn7patientswithdelayedorlateonsetofSCIDduetoADAdeficiencySantistebanetal(1993)identifiedmutationsintheADAgene(seeeg6089580020and6089580032)PartialADADeficiencyIn7patientswithpartialADAdeficiencyidentifiedbyaNewYorkStatenewbornscreeningprogramHirschhornetal(1990)identifiedmutationsintheADAgene(60895800106089580015)Sixofthe7childreneithercamefromalimitedareaintheCaribbeanorsharedablackethnicbackgroundsuggestingafoundereffecthoweverthefindingofmultiplenewmutationssuggestedthatpartialADAdeficiencyofferedaselectiveadvantageGeneReversionHirschhornetal(19941996)describedunusualcasesofsomaticmosaicismduetoinvivoreversiontonormalofaninheritedmutationintheADAgene(60895800246089580032)POPULATIONGENETICSBymeansofanewandspecificmethodSpenceretal(1968)demonstratedisozymesoferythrocyteadenosinedeaminaseandshowedthatthereare3geneticallydeterminedphenotypesADA1ADA2/1andADA2ThefrequencyoftheADA2allelewasestimatedat006inEuropeans004inBlacksand011inAsiaticIndiansDataongenefrequenciesofallelicvariantsweretabulatedbyRoychoudhuryandNei(1988)ANIMALMODELInmiceoverexpressingIl13(147683)inthelungBlackburnetal(2003)observedpulmonaryinflammationandremodelingaccompaniedbyaprogressiveincreaseinadenosineaccumulationinhibitionofADAactivityandmRNAaccumulationandincreasedexpressionofseveraladenosinereceptors(see102776)AdaenzymetherapydiminishedtheIl13inducedincreaseinadenosineinhibitedIl13inducedinflammationchemokineelaborationfibrosisandalveolardestructionandprolongedthesurvivalofIl13transgenicmiceIl13wasstronglyinducedbyadenosineinAdanullmiceBlackburnetal(2003)concludedthatadenosineandadenosinesignalingcontributetoandinfluencetheseverityofIL13inducedtissueresponsesandthatIL13andadenosinestimulateoneanotherinanamplificationpathway(selectedexamples)0001SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADALYS80ARG]InapatientwithSCIDduetoADAdeficiency(102700)originallyreportedbyHirschhornetal(1975)Valerioetal(1986)identifiedcompoundheterozygosityfor2mutationsintheADAgenelys80toarg(K80R)andL304R(6089580005)0002SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAARG101TRP]InapatientwithSCIDduetoADAdeficiency(102700)Akesonetal(1988)identifiedcompoundheterozygosityfor2mutationsintheADAgeneaCtoTtransitionresultinginanarg101totrp(R101W)substitutionandR211H(6089580004)FunctionalexpressionstudiesshowedthatthemutantgenesweretranscribedintonormalmRNAbutdidnotencodefunctionalproteinsInTcellsfromthepatientreportedbyAkesonetal(1988)withtheR101WandR211HmutationsArredondoVegaetal(1990)foundthattheR101WmutationcouldbeexpressedselectivelyinIL2dependentTcellsasastableactiveenzymeCulturedTcellsfromotherpatientswiththeR211HmutationdidnotexpresssignificantADAactivitywhereassomeBcelllinesfromapatientwithanR101Q(6085980003)mutationhadnormalADAactivityArredondoVegaetal(1990)speculatedthatarg101maybeatasitethatdeterminesdegradationofADAbyaproteasethatisundernegativecontrolbyIL2inTcellsandisvariablyexpressedinBcells0003SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAARG101GLN]InacelllinefromapatientwithSCIDduetoADAdeficiency(102700)Bonthronetal(1985)identifiedaGtoAtransitioninexon4oftheADAgeneresultinginanarg101togln(R101Q)substitutionSincethepredictedprimarystructureoftheenzymewasnormalthemutationwasapparentlyresponsibleforlossoffunctioninthegene0004SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAARG211HIS]InapatientwithSCIDduetoADAdeficiency(102700)Akesonetal(1987)identifiedcompoundheterozygosityfor2mutationsintheADAgeneaGtoAtransitioninexon7resultinginanarg211tohis(R211H)substitutionandA329V(6089580006)InanotherSCIDpatientAkesonetal(1988)identifiedcompoundheterozygosityfortheR211HandR101W(6089580002)mutationsFunctionalexpressionstudiesshowedthatthemutantgenesweretranscribedintonormalmRNAbutdidnotencodefunctionalproteinsIna5yearoldJapanesemalepatientwithSCIDduetoADAdeficiencyOnoderaetal(1998)identifiedtheR211Hsubstitutioncausedbya632GAtransitionintheADAgeneThepatienthadbeenreceivingperiodicinfusionsofgeneticallymodifiedautologousTlymphocytescarryingthetransducedADAgeneADAenzymeactivityinthepatient'scirculatingTcellswhichwasonlymarginallydetectedbeforegenetransferincreasedtolevelscomparabletothoseofaheterozygotecarrierandwasassociatedwithincreasedTlymphocytecountsandimprovementofthepatient'simmunefunction0005SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADALEU304ARG]InapatientwithSCIDduetoADAdeficiency(102700)originallyreportedbyHirschhornetal(1975)Valerioetal(1986)identifiedcompoundheterozygosityfor2mutationsintheADAgeneaTtoGtransversioninexon10resultinginaleu304toarg(L304R)substitutionandK80R(6089580001)FunctionalexpressionstudiesshowedthattheL304RsubstitutionresultedinADAenzymeinactivation0006SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAALA329VAL]InapatientwithSCIDduetoADAdeficiency(102700)Akesonetal(1987)identifiedcompoundheterozygosityfor2mutationsintheADAgenea1081CTtransitioninexon11resultinginanala329toval(A329V)substitutionandR211H(6089580004)AsecondpatientwascompoundheterozygousforA329Vandadeletionofexon4(6089580017)FunctionalexpressionstudiesshowedthatthemutantgenesweretranscribedintonormalmRNAbutdidnotencodefunctionalproteinsInaSCIDpatientMarkertetal(1989)identifiedtheA329Vmutationinexon11oftheADAgeneTheauthorsfoundthat5of13patients(7of22alleles)hadthesameA329VmutationandthatA329Vwasassociatedwith3distinctADAhaplotypesThefindingsdidnotsupportafoundereffectHirschhornetal(1992)foundthat5missensemutationsaccountedforonethirdof45ADAnegativechromosomesstudiedTheA329Vmutationwasthemostfrequentbeingfoundin4personsheterozygousforthemutationand1personhomozygousforthemutation(6/45alleles)0007REMOVEDFROMDATABASE0008SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADA325KBDELALURELATED]InaBelgianfemaleinfantwithSCIDandADAdeficiency(102700)bornofconsanguineousparentsBerkvensetal(1987)identifiedahomozygous32kbdeletionspanningthepromoterandthefirstexonoftheADAgeneNoADAspecificmRNAwasdetectedinthepatient'sfibroblastsindicatinganullalleleBothparentsandanunaffectedbrotherwereheterozygousforthemutationMarkertetal(1988)identifieda33kbdeletionintheADAgeneinanAmericanpatientwithADAdeficiencyandSCIDwhohadnolymphocyteADAenzymeactivitynodetectableADAmRNAandadeletionintheregionofthefirstexonoftheADAgeneMarkertetal(1988)determinedthatthedeletionoftheADApromoterandfirstexonresultedfromhomologousrecombinationbetween2repetitiveDNAsequencesoftheAlufamilyBydirectsequencingBerkvensetal(1990)showedthatthe325kbdeletionwasduetorecombinationwithintheleftarmsof2directAluIrepeatsTheynotedthatthemutationwasidenticaltothatintheunrelatedpatientreportedbyMarkertetal(1988)howeverneitherthepedigreeoftheBelgianfamilynoracomparisonofhaplotypedatasuggestedarelationshipbetweentheAmericanandBelgianpatientsInapatientwithSCIDduetoADAdeficiencyJiangetal(1997)identifiedcompoundheterozygosityfortheexon1deletionand2mutationsonthesameallele(6089580029)Threeof4additionalunrelatedpatientstestedhadtheexon1deletionsuggestingthatitisrelativelycommonTheauthorsnotedthattheexon1deletionaccountedfor10%ofalmost100chromosomesstudiedbyseverallaboratoriesbutwaseasilymissedbygenerallyusedmethodsofmutationdetection0009ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADAPRO297GLN]In2unrelatedpatientswithpartialADAdeficiency(102700)whowereimmunocompetentHirschhornetal(1989)identifiedaCtoAtransversioninexon10oftheADAgeneresultinginapro297togln(P297Q)substitutionOnepatientwashomozygousforthemutationandtheotherwascompoundheterozygousTheP297Qmutationresultedinaheatlabileenzyme0010ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADAARG76TRP]In3patientswithpartialADAdeficiencywholackedADAactivityinerythrocytesbutretainedADAactivityinlymphocytes(102700)Hirschhornetal(1990)identifieda226CTtransitioninexon4oftheADAgeneresultinginanarg76totrp(R76W)substitutionTheR76Wmutantalleleresultedinanabnormallyacidicproteinwith16%normalactivityinlymphoidcellsOnepatientwashomozygousandtheother2werecompoundheterozygous(seealso6089580012and6089580013)All3patientswerefromtheWestIndiesandtheauthorspostulatedaselectiveadvantageofcarryingamutantalleleforpartialADAdeficiency0011ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADAARG149GLN]InapatientwithpartialADAdeficiency(102700)Hirschhornetal(1990)identifieda446GAtransitionintheADAgeneresultinginanarg149togln(R149Q)substitutionTheR149Qmutantalleleresultedinamildlyacidicproteinwith42%residualactivity0012ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADAPRO274LEU]InapatientwithpartialADAdeficiency(102700)Hirschhornetal(1990)identifiedcompoundheterozygosityfor2mutationsintheADAgenean821CTtransitioninexon9resultinginapro274toleu(P274L)substitutionandR76Y(6089580010)TheP274Lmutantalleleresultedinanabnormallybasicproteinwith12%normalactivityinlymphoidcells0013SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADALEU107PRO]In2unrelatedpatientswithSCIDduetoADAdeficiency(102700)Hirschhornetal(1990)identifieda320TCtransitioninexon4oftheADAgeneresultinginaleu107topro(L107P)substitutionAnalysisofenzymeactivityshowedthattheL107Pmutationisanullallele0014ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADAARG211CYS]InapatientwithpartialADAdeficiency(102700)Hirschhornetal(1990)identifiedcompoundheterozygosityfor2mutationsintheADAgenea631CTtransitionresultinginanarg211tocys(R211C)substitutionandL107P(6089580013)TheR211Cmutantalleleresultedinanabnormallyacidicproteinwith8%normalactivityinlymphoidcellsIn2sisterswithadultonsetADAdeficiencyShovlinetal(1994)identifiedcompoundheterozygosityfor2mutationsintheADAgeneThepaternalallelecontainedadeletionresultingfromhomologousrecombinationbetween2AluelementspredictinganullphenotypeThematernalallelehadaCtoTtransitioninaCpGdinucleotidethatchangedthecodonforarginine211whichliesinaconservedsequenceclosetotheactivesitetocysteineThismutationhadpreviouslybeenobservedinachildthoughttohavepartialADAdeficiencybyHirschhornetal(1990)(6089580013)Shovlinetal(1994)suggestedthatimmunefunctioninchildrenwithpartialADAdeficiencymaydeterioratewithtime0015ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADAALA215THR]InapatientwithpartialADAdeficiency(102700)Hirschhornetal(1990)identifiedahomozygous643GAtransitioninexon7oftheADAgeneresultinginanala215tothr(A215T)substitutionTheA215Tmutantalleleresultedinanabnormallybasicproteinwith8%residualactivityinlymphoidcells0016SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAGLY216ARG]InapatientwithSCIDduetoADAdeficiency(102700)Hirschhornetal(1991)identifiedahomozygous646GAtransitioninexon7oftheADAgeneresultinginagly216toarg(G216R)substitutionThepatientwastheoffspringofconsanguineousAmishparentsfromeasternPennsylvaniaComputeranalysisofsecondarystructurepredictedamajoralterationwithlossofabetapleatedsheetinahighlyconservedregionoftheproteinOnsetofsymptomswasat3daysofagewithrespiratorydistressfrompneumoniaunresponsivetoantibioticsOf9patientsthisonehadthehighestconcentrationofthetoxicmetabolitedeoxyATPandarelativelypoorimmunologicresponseduringtheinitial2yearsoftherapywithpolyethyleneglycoladenosinedeaminaseHeterozygosityforthesamemutationwasfoundin2of21additionalpatientswithADASCID0017SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAIVS3ASAG2EX4DEL]InapatientwithSCIDduetoADAdeficiency(102700)Akesonetal(1987)identifiedcompoundheterozygosityfor2mutationsintheADAgeneadeletionofexon4andA329V(6089580006)Akesonetal(1988)foundthattheexon4deletionwascausedbyanAtoGtransitioninthe3primesplicesiteofintron3FunctionalexpressionstudiesshowedthatthemutantgenewastranscribedintonormalmRNAbutdidnotencodeafunctionalprotein0018SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAARG156CYS]InapatientwithSCIDduetoADAdeficiency(102700)whowasunusualforrespondingtothelimitedformofenzymetherapyprovidedbyrepeatedpartialexchangetransfusions(Polmaretal1976Dyminskietal1979)Hirschhorn(1992)identifiedcompoundheterozygosityfor2mutationsintheADAgenea466CTtransitionresultinginanarg156tocys(R156C)substitutionandL304R(6089580005)0019SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADASER291LEU]InapatientwithSCIDduetoADAdeficiency(102700)whowasunusualforrespondingtothelimitedformofenzymetherapyprovidedbyrepeatedpartialexchangetransfusions(Polmaretal1976Dyminskietal1979)Hirschhorn(1992)identifiedcompoundheterozygosityfor2mutationsintheADAgenean872CTtransitioninexon10resultinginaser291toleu(S291L)substitutionandA329V(6089580006)0020SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCYLATEONSET[ADAIVS10ASGA34]InapatientwithlateonsetSCIDduetoADAdeficiency(102700)inwhomthediagnosisofADAdeficiencywasfirstmadeattheageof15yearsSantistebanetal(1993)identifiedahomozygous34GAtransitioninintron10oftheADAgeneconvertingaGGdinucleotidetoAGresultinginanewspliceacceptorsitewithallthecisactingelementsofafunctional3primesplicejunctionBesidesintroducing9newcodonsafterleu325useofthecrypticsplicesiteshiftedthereadingframetoinclude268bpofthenormal3primenoncodingregionbeforeanewTGAstopcodonwasgenerated16bpfromthepoly(A)additionsignalThemutantproteinwaspredictedtoconsistof463residuescomparedtothenormal363residues0021ADENOSINEDEAMINASE2ALLOZYME[ADAASP8ASN]Hirschhornetal(1994)determinedthatthecommonelectrophoreticvariantofADAtheADA2allozyme(ADA*2)iscausedbya22GAtransitionintheADAgeneresultinginanasp8toasn(D8N)substitutionTheADA2allozymeisamorebasicelectrophoreticvariantthatiscodominantlyinheritedwiththeusualADA1allozymeFunctionalexpressionstudiesoftheD8NproteinconfirmedexpressionofanenzymethatcomigratedwithanaturallyoccurringADA2allozymeHirschhornetal(1994)notedthattheADA2allozymehasbeenfoundinallpopulationsstudiedandresultsinonlyminimallyreducedenzymeactivityinerythrocytesThegenefrequencyoftheADA2allozymeisestimatedas006inWesternpopulationsloweramongindividualsofAfricandescentandhigherinSoutheastAsianpopulationsTheADA2allelewasalsofoundonatleast2differentgeneticbackgrounds1ofAshkenaziJewishancestryand1inalargeMormonpedigreefromUtahsuggestingindependentrecurrenceofthemutationConsistentwithindependentrecurrencetheGtoAtransitionwaslocatedinaCpGdinucleotideofthetypesubjecttoahighfrequencyofmutationHirschhornetal(1994)alsofoundaprobableintrageniccrossoverintheverylargefirstintronthatisrichinrepetitiveDNAsequencesIn2ItaliangroupsofautisticchildrenBottinietal(2001)foundasignificantlyhigherfrequencyofthelowactivityADA2allelethanincontrolsTheysuggestedthatthisgenotypedependentreductioninADAactivitymaybeariskfactorforthedevelopmentofautism0022SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAIVS2DSGA+1]In2sisterswithSCIDduetoADAdeficiencyreportedbyUmetsuetal(1994)ArredondoVegaetal(1994)identifiedcompoundheterozygosityfor2splicesitemutationsintheADAgeneaGtoAtransitionatthe+1positionofthe5primesplicesiteofIVS2andacomplex17bprearrangementofthe3primesplicesiteofIVS8resultingina7purineinsertionintothepolypyrimidinetractandalterationofthereadingframeofexon9(6089580023)ThesistersshowedadisparityinclinicalphenotypewithresidualADAactivityinculturedTcellsfibroblastsandBlymphoblastsofonebutnodetectableactivityinthecellsoftheotherADAmRNAwasundetectablebyNorthernblotanalysisinthecellsofbothpatientsPCRamplifiedADAcDNAmutantclonesshowedprematuretranslationstopcodonsconsistentwiththesemutationsHoweversomecDNAclonesfromTcellsofbothpatientsandfromfibroblastsandEBVtransformedBcellsofthefirstpatientwerenormallysplicedatboththeexon2/3and8/9junctionsAnormalcodingsequencewasdocumentedforclonesfrombothsibsArredondoVegaetal(1994)suggestedthatalowlevelofnormalpremRNAsplicingmayoccurdespitemutationoftheinvariantfirstnucleotideofthe5primesplicedonorsequenceandthatdifferencesinefficiencyofsuchsplicingmayaccountforthedifferenceinresidualADAactivityimmunedysfunctionandclinicalseverityinthe2sibs0023SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADA7BPINSIVS8AS]See6089580022andArredondoVegaetal(1994)0024SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAIVS1DSGC+1]Ina25yearoldpatientwithSCIDduetoADAdeficiency(102700)Hirschhornetal(1994)identifiedcompoundheterozygosityfor2mutationsintheADAgenea+1GCtransversionatthedonorsplicesiteinIVS1andR101Q(6089580003)Thepatient'sdiseasecourseimprovedandhewashealthybyage16yearsCelllinesestablishedatage16showed50%ofnormalADAactivity50%ofADAmRNAhadnormalsequenceand50%hadtheR101QmutationGenomicDNAcontainedthemissensemutationbutnotthesplicesitemutationTheauthorspostulatedsomaticmutationorreversionatthesiteofthemutation0025SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAGLY74VAL]InanewbornwithhepaticdysfunctionasacomplicationofSCIDduetoADAdeficiency(102700)Bollingeretal(1996)identifiedcompoundheterozygosityfor2mutationsintheADAgeneaGtoTtransversionresultinginagly74toval(G74V)substitutionandA329V(6089580006)0026SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCY[ADAIVS5DSGA+1]InapatientwithamildformofSCIDduetoADAdeficiency(102700)Hirschhornetal(1996)identifiedcompoundheterozygosityfor2mutationsintheADAgeneaGtoAtransitioninintron5resultingindeletionofexon5andR156H(6089580032)ThesplicesitemutationwasinheritedfromthefatherandtheR156Hmutationwasinheritedfromthemother0027ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADALEU152MET]InanAfghaniboywithpartialADAdeficiency(102700)identifiedthroughnewbornscreeninginNewYorkStateHirschhornetal(1997)identifiedahomozygous454CAtransversionoftheADAgeneresultinginaleu152tomet(L152M)substitutionThechildwasbornofconsanguineousparentsFunctionalexpressionstudiesshowedthattheL152MmutationhadconsiderablylessenzymaticactivitythanthepathogenicR211C(6089580014)mutationThechildhadthehighestleveloftheaccumulatedmetabolitedATPamongthe13partiallyADAdeficientpatientsstudiedbutconsiderablylessdATPthanthosewithimmunodeficiencyTheauthorsconcludedthattheL152Mmutationcouldresultindiseaseinhomozygousindividualschallengedbysevereenvironmentalinsultorinheterozygousindividualswhencombinedwithanullmutation0028ADENOSINEDEAMINASEDEFICIENCYPARTIAL[ADATHR233ILE]InahealthyadultmaleofAfghaniKungdescentwithpartialADAdeficiency(102700)Hirschhornetal(1997)identifiedahomozygous698CTtransitionintheADAgeneresultinginathr233toile(T233I)substitutionFunctionalexpressionstudiesshowedthattheT233Imutationhad16to20%normalenzymeactivitywhichwasslightlygreaterthanthepathogenicR211C(6089580014)mutationImmunologicstudiesdonepreviouslyonthepatientindicatedanunstableADAenzymethatwasabsentinredbloodcellsbutpresentinsufficientamountsinothercelltypestopreventaccumulationoftoxicmetabolitesandresultingimmunodeficiency0029SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCYBCELLNEGATIVENKCELLNEGATIVEDUETOADADEFICIENCY[ADATYR97CYSANDLEU106VAL]InapatientwithSCIDduetoADAdeficiency(102700)Jiangetal(1997)identifiedcompoundheterozygosityfor2mutantADAallelesOnealleleinheritedfromthemothercontained2mutationsinexon4a290AGtransitionresultinginatyr97tocys(Y97C)substitutionanda316CGtransversionresultinginaleu106toval(L106V)substitutionThesecondalleleinheritedfromthefatherwasadeletion(6089580008)ThepatientwasdiagnosedprenatallyinafamilywithanaffectedchildpreviouslyreportedbyMoenetal(1987)andthediagnosiswasconfirmedafterbirthbydemonstrationoflessthan1%ADAactivityinredbloodcellsandmononuclearcellsFunctionalexpressionstudiesshowedthattheL106Vmutationresultedin30%ofnormalactivitysimilartothatofpartialmutationsandtheY97Cmutationresultedin15%ofnormalactivityThepresenceofbothmutationsonthesameallelevirtuallyabolisheddetectableenzymeactivitytolessthan001%CrystallographicstructureanalysisshowedthattheL106VmutationsurroundstheopeningoftheactivesiteandispredictedtoreducethestabilityofsubstratebindingTheY97CmutationresideswithintheactivesiteandinteractswithsaltridgesthatplayaroleinthecatalyticmechanismofADA0030SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCYDELAYEDONSET[ADAIVS11AS31701TA]In4patientsfrom3SaudiArabianfamilieswithdelayedonsetofimmunedeficiency(102700)ArredondoVegaetal(2002)identifiedhomozygosityfora31701TAtransversioninthelastspliceacceptorsiteoftheADAgeneByconvertingTGtoAGthismutationactivatedacrypticsplicesiteinsertingthelast13nucleotidesofintron11intoADAmRNAwhichresultedinadditionofa43residueCterminaltailthatrenderedtheproteinunstableWhenmutantcDNAfrom3patientswasexpressedinEcolionly1%oftheADAactivityobtainedwithwildtypecDNAwasyieldedTheoldestpatient16yearsoldatdiagnosishadgreaterresidualimmunefunctionandlesselevatederythrocytedeoxyadenosinenucleotidesthanhis4yearoldaffectedsisterInadditiontobeinghomozygousfortheintron11mutationhealsocarriedadeletionof11adjacentdownstreamnucleotides(6089580031)0031SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCYLATEONSET[ADAIVS11AS31701TAAND11BPDELNT31702]InapatientwithlateonsetofSCIDduetoADAdeficiency(102700)whowasdiagnosedatage16yearsArredondoVegaetal(2002)identifiedthehomozygousintron11mutation(6089580030)andan11bpdeletionofadjacentbasepairs3170231712whichsuppressedaberrantsplicingandexcisedanunusualpurinerichtractfromthewildtypeintron11/exon12junctionDespiteserioussequelaeofearlyinfectionsthispatienthadapparentlystabilizedatsometimeduringchildhoodHisTcellsandEpsteinBarrvirus(EBV)Bcelllinehad75%ofnormalADAactivityandADAproteinofnormalsizeTheauthorsnotedthatthemildatypicalfeaturesofthispatientwerecausedbyanunusualformofsomaticreversionsecondsitesuppressionofacrypticsplicesiteHoweverafterseveralmonthsofPEGADAtreatmentthepatienthadlowerADAactivitythanbeforetreatmentandtheauthorssuggestedthattherapyallowedtheADAdeficientlymphoidcellstosurviveandproliferate0032SEVERECOMBINEDIMMUNODEFICIENCYAUTOSOMALRECESSIVETCELLNEGATIVEBCELLNEGATIVENKCELLNEGATIVEDUETOADENOSINEDEAMINASEDEFICIENCYLATEONSET[ADAARG156HIS]In3patientswithdelayedorlateonsetofSCIDduetoADAdeficiency(102700)Santistebanetal(1993)identifiedaheterozygous467GAtransitioninexon5oftheADAgeneataCpGhotspotresultinginanarg156tohis(R156H)substitutionAll3patientswerecompoundheterozygousforR156Handamutationpredictedtoresultinaninactiveenzyme1patientalsocarriedtheG216R(6089580016)mutationFunctionalexpressionstudiesshowedthattheR156Hmutantenzymeretained15to2%residualactivityInapatientwithamildformofSCIDduetoADAdeficiencyHirschhornetal(1996)identifiedcompoundheterozygosityfortheR156Hmutationinheritedfromthemotherandasplicesitemutation(6089580026)inheritedfromthefatherThepatientshowedclinicalimprovementwithouttherapyandanalysisattheageof11yearsrevealedthattheR156HmutationhadundergoneinvivoreversiontonormalinlymphoidcelllinesandinasubsetofperipheralbloodcellsTheauthorsconcludedthatthesomaticmosaicismcausedtherelativelymildphenotypeSEEALSOAbbottetal(1986)Adrianetal(1984)AitkenandFergusonSmith(1978)Akesonetal(1989)Blackburnetal(1998)Markertetal(1987)Orkinetal(1983)TariverdianandRitter(1969)Valerioetal(1984)Wigintonetal(1984)REFERENCES1AbbottCMSkidmoreCJSearleAGPetersJDeficiencyofadenosinedeaminaseinthewastedmouseProcNatAcadSci836936951986PubMedID34561642AdrianGSHuttonJJAdenosinedeaminasemessengerRNAsinlymphoblastcelllinesderivedfromleukemicpatientsandpatientswithhereditaryadenosinedeaminasedeficiencyJClinInvest71164916601983PubMedID61347543AdrianGSWigintonDAHuttonJJCharacterizationofnormalandmutantadenosinedeaminasemessengerRNAsbytranslationandhybridizationtoacDNAprobeHumGenet681691721984PubMedID65487264AdrianGSWigintonDAHuttonJJStructureofadenosinedeaminasemRNAsfromnormalandadenosinedeaminasedeficienthumancelllinesMolecCellBiol4171217171984PubMedID62084795AitkenDAFergusonSmithMAInvestigationoftheintrachromosomalpositionoftheADAlocusonchromosome20bygenedosagestudiesCytogenetCellGenet225145171978PubMedID7525336AkesonALWigintonDADusingMRStatesJCHuttonJJMutanthumanadenosinedeaminaseallelesandtheirexpressionbytransfectionintofibroblastsJBiolChem26316291162961988PubMedID31827937AkesonALWigintonDAHuttonJJNormalandmutanthumanadenosinedeaminasegenesJCellBiochem392172281989PubMedID26514618AkesonALWigintonDAStatesJCPermeCMDusingMRHuttonJJMutationsinthehumanadenosinedeaminasegenethataffectproteinstructureandRNAsplicingProcNatAcadSci84594759511987PubMedID34757109ArredondoVegaFXKurtzbergJChaffeeSSantistebanIReisnerEPoveyMSHershfieldMSParadoxicalexpressionofadenosinedeaminaseinTcellsculturedfromapatientwithadenosinedeaminasedeficiencyandcombinedimmunodeficiencyJClinInvest864444521990PubMedID197455410ArredondoVegaFXSantistebanIKellySSchlossmanCMUmetsuDTHershfieldMSCorrectsplicingdespitemutationoftheinvariantfirstnucleotideofa5primesplicesiteapossiblebasisfordisparateclinicalphenotypesinsiblingswithadenosinedeaminasedeficiencyAmJHumGenet548208301994PubMedID817882111ArredondoVegaFXSantistebanIRichardEBaliPKoleilatMLoubserMAlGhonaiumAAlHelaliMHershfieldMSAdenosinedeaminasedeficiencywithmosaicismfora'secondsitesuppressor'ofasplicingmutationdeclineinrevertantTlymphocytesduringenzymereplacementtherapyBlood99100510132002PubMedID1180700612BerkvensTMGerritsenEJAOldenburgMBreukelCWijnenJTvanOrmondtHVossenJMvanderEbAJMeeraKhanPSeverecombinedimmunedeficiencyduetoahomozygous32kbdeletionspanningthepromoterandfirstexonoftheadenosinedeaminasegeneNucleicAcidsRes15936593781987PubMedID368459713BerkvensTMvanOrmondtHGerritsenEJAMeeraKhanPvanderEbAJIdentical3250bpdeletionbetweentwoAluIrepeatsintheADAgenesofunrelatedADASCIDpatientsGenomics74864901990PubMedID169692614BlackburnMRDattaSKKellemsREAdenosinedeaminasedeficientmicegeneratedusingatwostagegeneticengineeringstrategyexhibitacombinedimmunodeficiencyJBiolChem273509351001998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