OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP0OMIMUniSTS0*313700GeneTestsLinksANDROGENRECEPTORARAlternativetitlessymbolsDIHYDROTESTOSTERONERECEPTORDHTRGenemaplocusXq11q12TEXTDESCRIPTIONThegeneencodingandrogenreceptor(AR)alternativelyknownasthedihydrotestosteronereceptorislocatedontheXchromosomeItismutantintheandrogeninsensitivitysyndrome(AIS300068)formerlyknownasthetesticularfeminizationsyndrome(TFM)andinKennedyspinalandbulbarmuscularatrophy(SBMA313200)Clinicalvariantsoftheandrogeninsensitivitysyndrome(partialandrogeninsensitivity)includetheReifensteinsyndrome(312300)TheARproteinbelongstotheclassofnuclearreceptorscalledactivatedclassIsteroidreceptorswhichalsoincludesglucocorticoidreceptor(GCCR138040)progesteronereceptor(PGR607311)andmineralocorticoidreceptor(NR3C2600983)Thesereceptorsrecognizecanonicalandrogenresponseelements(AREs)whichareinvertedrepeatsof5primeTGTTCT3primeThemajordomainsofARincludeNandCterminalactivationdomainswhicharedesignatedactivationfunction1(AF1)andAF2aligandbindingdomainandapolyglutaminetract(Callewaertetal2003)CLONINGChangetal(1988)andLubahnetal(1988)clonedhumanandrogenreceptorcDNAsLubahnetal(1988)determinedthecompletecodingsequenceofthehumanandrogenreceptorandcomparedthededuced919aminoacidsequence(98999Da)tothe902aminoacidsequenceofratAR(98227Da)IdenticalsequenceswerefoundintheDNAandhormonebindingdomainswithanoverallhomologyof85%Changetal(1988)obtainedcDNAsfromhumantestisandratventralprostatecDNAlibrariesThededucedaminoacidsequenceindicatedthepresenceofacysteinerichDNAbindingdomainthatishighlyconservedinallsteroidreceptorsThehumancDNAwastranscribedandtheRNAproducttranslatedincellfreesystemstoyielda76kDproteinTheproteinwasimmunoprecipitablebyhumanautoimmuneantibodiestotheandrogenreceptoranditboundandrogensspecificallyandwithhighaffinity(Someoldermenwithprostatecancerhavehightitersofautoimmuneantibodiestoandrogenreceptor(LiaoandWitte1985))BothChangetal(1988)andLubahnetal(1988)usedARasthesymbolforandrogenreceptorTheandrogenreceptorgeneismorethan90kblongandcodesforaproteinthathas3majorfunctionaldomainsTheNterminaldomainwhichservesamodulatoryfunctionisencodedbyexon1(1586bp)TheDNAbindingdomainisencodedbyexons2and3(152and117bprespectively)Theandrogenbindingdomainisencodedby5exonswhichvaryfrom131to288bpinsizeInhumanprostatethemajorARmRNAspeciesis10kbwhereasalessabundantmRNAisapproximately7kb(Lubahnetal1988)IntheprostateARislocalizedpredominantlytonucleiofgranularepithelialcellsTilleyetal(1989)isolatedacDNAthatencodesthecompletehumanARgeneThecDNApredictedaproteinof917aminoacidswithamolecularmassofof98918DaIntroductionofthecDNAintoheterologousmammaliancellscausedexpressionofhighlevelsofaproteinthatbindsdihydrotestosteronewiththeaffinityspecificityandsedimentationpropertiescharacteristicofthenativereceptorComparisonwiththeaminoacidsequenceofpreviouslyclonedsteroidhormonereceptorsshowedahighdegreeofsequenceconservationwiththeprogesteroneglucocorticoidandmineralocorticoidreceptorsintheputativehormoneandDNAbindingdomainsTwonaturallyoccurringhormonebindingformsofprogesteronereceptor(607311)havebeenidentifiedTheAisoformisanNterminallytruncatedversionofthefulllengthBisoformSeverallinesofevidencesuggestthatthe2isoformsservespecificfunctionsWilsonandMcPhaul(1994)demonstrated2formsoftheandrogenreceptorproteininhumangenitalskinfibroblastsTheapparentmolecularmasseswereapproximately110kDand87kDThe87kDisoform(ARA)containedanintactCterminusbutlackedthenormalNterminusfoundinthe110kDisoform(ARB)ARAisthesamesizeasthemutantformofARproducedinfibroblastsfromanandrogenresistantindividualbyinitiationofARsynthesisatthefirstinternalmet188residueofARBasreportedbyZoppietal(1993)TheARisoformsresembledtheAandBformsoftheprogesteronereceptorwhichalsoareencodedbyasinglegeneanddifferbytheabsenceorpresenceofanNterminalsegmentTheAandBformsoftheprogesteronereceptordifferintheirabilitytoactivatetargetgenesandareregulateddifferentlyinvarioustypesofcellsTheidentificationofsimilarformsofARraisedthepossibilitythatthe2isoformsalsoservedifferentfunctionsGENEFUNCTIONKangetal(1999)demonstratedthattheARA54gene(RNF14605675)canfunctionasacoactivatorforandrogendependenttranscriptiononbothwildtypeandmutantandrogenreceptorInthepresenceofacertainamountof17betaestradiolorhydroxyflutamidethetranscriptionalactivityofaspecificARmutantwassignificantlyenhancedwhereasthatofwildtypeandanotherARmutantwasnotTheythereforesuggestedthatbothARA54andthepositionsoftheARmutationmightcontributetothespecificityofARmediatedtransactivationCoexpressionofARA54withotherARcoactivatorssuchasARA70(NCOA4601984)andSRC1(NCOA1602691)showedadditivestimulationofARmediatedtransactivationindicatingthatthesecofactorsmayfunctionindividuallyasARcoactivatorstoinduceARtargetgeneexpressionSullivanetal(2000)demonstratedthattheandrogenreceptorproteinexistswithinacinarepithelialcellnucleioftheratmeibomianglandInstudiesinratsandrabbitstheyfoundevidencethatthemeibomianglandisanandrogentargetorganandthatandrogensinfluencethelipidprofilewithinthistissueShangetal(2002)describeddistinctfunctionsforcofactorproteinsandgeneregulatoryelementsintheassemblyofARmediatedtranscriptioncomplexesTheformationofanactivationcomplexinvolvesARcoactivatorsandRNApolymeraseII(polIIsee180660)recruitmenttoboththeenhancerandpromoterwhereastheformationofarepressioncomplexinvolvesfactorsboundonlyatthepromoterandnottheenhancerTheresultssuggestedamodelforthefunctionalcoordinationbetweenthepromoterandenhancerinwhichcommunicationbetweentheseelementsisestablishedthroughsharedcoactivatorsintheARtranscriptioncomplexLeeetal(2003)hypothesizedthatARmaymodulategeneexpressionbyenhancingtheefficiencyoftranscriptionalelongationTheydemonstratedthatcoexpressionofthesecondlargestsubunitofRNApolymeraseIIRPB2(POLR2B180661)enhancedARtransactivationCoexpressionwithotherRNApolymeraseIIsubunitsorTFIIB(GTF2B189963)didnotenhanceARmediatedtranscriptionLeeetal(2003)concludedthatARmayinteractwithTFIIH(see189968)PTEFb(seeCCNT2603862)andRPB2toenhancetranscriptionfromARtargetgenesMetzgeretal(2003)foundthatARandPRK1(PRKCL1601032)interactedinvitroandinvivoStimulationofthePRK1signalingcascaderesultedinliganddependentsuperactivationofARinhumanprostatecarcinomacellsandPRK1promotedafunctionalcomplexofARwiththecoactivatorTIF2(NCOA2601993)PRK1signalingstimulatedARactivityinthepresenceofadrenalandrogensandinthepresenceofanARantagonistMetzgeretal(2003)concludedthatARiscontrolledbyPRK1signalingaswellasbyligandbindingCallewaertetal(2003)foundthatdeletionofthepolyglutaminetractwithintheNterminaldomainofARincreasedtransactivationofthereceptorthroughcanonicalAREsandtheeffectappearedduetotighterinteractionbetweentheNandCterminaldomainsofARDeletionofthepolyglutaminetractalsoincreasedrecruitmentofSRC1totheNterminaldomainofARTransactivationofselectiveAREswhichcontaindirectratherthaninvertedrepeatsof5primeTGTTCT3primewerenotinfluencedbydeletionoftheARpolyglutaminetractCallewaertetal(2003)hypothesizedthatARtranscriptionalactivityonselectiveAREsdoesnotdependoninteractionbetweentheNandCterminaldomainsofARUsingmicroarrayanalysisofratventralprostateRNAfollowing5alphadihydrotestosteronetreatmentNantermetetal(2004)foundthatARrapidlymodulatedtheexpressionofgenesinvolvedinproliferationanddifferentiationARrepressedexpressionofseveralkeycellcycleinhibitorswhilemodulatingmembersoftheWnt(see164820)andNotch(see190198)signalingpathwaysmultiplegrowthfactorspeptidehormonesignalingsystemsandgenesinvolvedinMAPkinaseandcalciumsignalingThedatasuggestedthatactivityofp53(191170)wasnegativelyregulatedbyARactivationeventhoughp53RNAwasunchangedUsingLNCaPcellsNantermetetal(2004)determinedthatARinhibitedp53proteinaccumulationinthenucleusprovidingaposttranscriptionalmechanismbywhichandrogenscontrolprostatecellgrowthandsurvivalBySDSPAGEandpeptidemassfingerprintingIshitanietal(2003)characterizedhumanembryonickidneycellnuclearproteinsthatinteractedwithpurifiedAF1ofARProteinsthatinteractedwithAF1includednuclearRNAbindingproteinNRB54(NONO300084)polypyrimidinetractbindingproteinassociatedsplicingfactor(PSForSFPQ605199)paraspeckleprotein1(PSP1)andPSP2whichareassumedtobeinvolvedinpremRNAprocessingBindingofNRB54toAF1wasliganddependentandAF1functionwaspotentiatedbyNRB54LeeandChang(2003)reviewedmechanismsimplicatedinthecontrolofARproteinexpressionanddegradationandtheirpotentialrelationshiptoandrogenrelateddiseasesMandrusiaketal(2003)foundthatandrogenreceptorNterminalfragmentsareasubstratefortransglutaminase(see190195)WesternblotsoftheproteinsfollowingincubationwithtransglutaminaseshowedlossofseveraldifferentepitopesoftheARsuggestiveoftransglutaminasecrosslinkingoftheARwhichinterfereswithantibodyrecognitionHEKGFPu1cellsexpressingpolyglutamineexpandedandrogenreceptorandtransglutaminaseexhibitedliganddependentproteasomedysfunctionthiseffectwasnotobservedinthepresenceofcystamineatransglutaminaseinhibitorInadditiontransglutaminasemediatedisopeptidebondsweredetectedinbrainsofSBMAtransgenicmicebutnotincontrolssuggestinginvolvementoftransglutaminasecatalyzedreactionsinpolyglutaminediseasepathogenesisMandrusiaketal(2003)hypothesizedthatcrosslinkedARcannotbedegradedbytheproteasomeandmayobstructtheproteasomeporepreventingnormalfunctionWangetal(2005)foundthatARregulationofPSA(KLK3176820)inLNCaPcellsinvolvedbothapromoterproximalsequenceandanenhancerabout4kbupstreamRecruitmentofARandessentialcoactivatorsatbothsitescreatedachromosomalloopthatallowedRNApolymeraseIItotrackfromtheenhancertothepromoterPhosphorylationoftheRNApolIICterminaldomainwasrequiredforRNApolIItrackingbutnotchromosomalloopingStudiesontheARProteinWithanExpandedPolyglutamineRepeatChoongetal(1996)foundaninverserelationshipbetweenARCAGrepeatlengthandARmRNAandproteinlevelsinaninvitromodelusingtransienttransfectionofhumanARexpressionvectorsTrinucleotiderepeatlengthsof43and65associatedwithXlinkedspinalandbulbarmuscularatrophydecreasedARmRNAandproteinlevelsbutdidnotalterequilibriumbindingaffinityforasyntheticandrogenortheARtranscriptionalactivityThesefindingsindicatedthatglutamateexpansionsofupto66residuesinthefirstARexondidnotalterARfunctionalactivitybutdidreduceARmRNAandproteinexpressionButleretal(1998)foundthattransfectionofanSBMAmutantandrogenreceptor(52CAGrepeats)intomouseneuroblastomacellsenhancedtheproductionofCterminallytruncatedfragmentsoftheandrogenreceptorproteinA74kDfragmentwasparticularlyprominentincellsexpressingtheSBMAandrogenreceptorFromitssizeitcouldbededucedthatthe74kDfragmentlackedthehormonebindingdomainbutretainedtheDNAbindingdomainThe74kDfragmentmaythereforebetoxictomotorneuronsbyinitiatingthetranscriptionofspecificgenesintheabsenceofhormonalcontrolImmunofluorescencemicroscopyontransfectedneuroblastomacellsshowedthatthewildtypeandrogenreceptortranslocatedtothenucleusafterhormoneactivationwhereastheSBMAandrogenreceptorwasmainlylocalizedinthecytoplasmintheformofdenseaggregateswithverylittleandrogenreceptorproteininthenucleusThefindingscouldexplainthereductionintranscriptionalactivityoftheSBMAmutantascomparedwithwildtypeandrogenreceptorKobayashietal(1998)showedthatinvitrotranslatedfulllengthARproteinscontainingdifferentsizedpolyglutaminerepeats(2465and97repeatsrespectively)werespecificallycleavedbyrecombinantcaspase3(CASP3600636)liberatingapolyglutaminecontainingfragmentandthatthesusceptibilitytocleavagewaspolyglutaminerepeatlengthdependentThesefindingssuggestedthattheARproteinisoneofthe'deathsubstrates'cleavedbycaspase3andthatcaspase3maybeinvolvedinthepathogenesisofSBMAMerryetal(1998)foundthattransfectionofatruncatedARproteinwithexpandedCAGrepeatsintoCOS7cellsresultedinincreasedcelldeathWesternblotanalysisshowedthattheexpandedproteinunderwentproteolyticcleavagewithinthepolyglutaminetractandformedintracellularaggregatesinarepeatlengthdependentmannerSimeonietal(2000)producedamodeltostudytheeffectsofpotentially'neurotoxic'polyglutamineaggregatesinSBMAusingimmortalizedmotoneuronalcellstransfectedwithARcontainingpolyglutaminerepeatsofdifferentsizes(zero23or46repeats)UsingchimerasofthemodifiedARproteinandthegreenfluorescentprotein(GFP)theyshowedthataggregateformationoccurswhenthepolyglutaminetractiselongatedandARisactivatedbyandrogensInthecellscoexpressingARwiththepolyglutamineofpathologiclength(46repeats)andtheGFPSimeonietal(2000)notedthepresenceofseveraldystrophicneuritesCellviabilityanalysesshowedareducedgrowth/survivalrateinthecellsexpressingthepolyglutamineofpathologiclengthwhereastestosteronetreatmentpartiallycounteractedbothcelldeathandtheformationofdystrophicneuritesTheseobservationsindicatedthelackofcorrelationbetweenaggregateformationandcellsurvivalandsuggestedthatneuronaldegenerationinSBMAmaybesecondarytoaxonal/dendriticinsultsMcCampbelletal(2000)demonstratedthatCREBbindingprotein(CREBBP600140)atranscriptionalcoactivatorthatorchestratesnuclearresponsetoavarietyofcellsignalingcascadesisincorporatedintonuclearinclusionsformedbypolyglutaminecontainingproteinsinculturedcellstransgenicmiceandtissuefrompatientswithSBMASolublelevelsofCREBbindingproteinwerereducedincellsexpressingexpandedpolyglutaminedespiteincreasedlevelsofCREBBPmRNAOverexpressionofCREBBPrescuedcellsfrompolyglutaminemediatedtoxicityinneuronalcellcultureTheauthorsproposedaCREBBPsequestrationmodelofpolyglutamineexpansiondiseaseWelchandDiamond(2001)usedthewildtypeglucocorticoidreceptor(GR138040)andamutatedformoftheGR(GRdelta109317)tostudyexpandedpolyglutamineARproteinindifferentcellcontextsTheauthorsfoundthatwildtypeGRpromotedsolubleformsoftheARproteinandpreventednuclearaggregationinNIH3T3cellsandculturedneuronsIncontrastGRdelta108317decreasedpolyglutamineproteinsolubilityandcausedformationofnuclearaggregatesinnonneuronalcellsNuclearaggregatesrecruitedtheheatshockproteinhsp72(HSPA1A140550)morerapidlythancytoplasmicaggregatesandwereassociatedwithdecreasedcellviabilityLimitedproteolysisandchemicalcrosslinkingsuggestedthatuniquesolubleformsoftheexpandedARproteinmayunderliethesedistinctbiologicactivitiesTheauthorshypothesizedthatuniqueproteinassociationsorconformationsofexpandedpolyglutamineproteinsmaydeterminesubsequentcellulareffectssuchasnuclearlocalizationandcellulartoxicityBaileyetal(2002)developedacellculturesystemwhichaffordedquantitativeanalysisoftheeffectsofmolecularchaperonesonthebiochemicalpropertiesofanexpandedrepeatARTheauthorsdemonstratedthatHsp70(see140550)anditscochaperoneHsp40(see604572)notonlyincreasedexpandedrepeatARsolubilitybutenhancedthedegradationofexpandedrepeatARthroughtheproteasomeFurthermorethesechaperonessignificantlydecreasedthehalflifeofanexpandedrepeatARsuggestingthatupregulationofmolecularchaperonesmaybeapotentialtherapeutictargetforpolyglutaminediseasesRNAinterferenceisamechanismthatappearstocontrolunwantedgeneexpressioninawiderangeofspeciesTotestifRNAinterferencecanbeusedtospecificallydownregulateahumandiseaserelatedtranscriptCaplenetal(2002)devisedDrosophilaandhumantissueculturemodelsofSBMAAvarietyofdifferentdoublestrandedRNAs(dsRNAs)wereassessedfortheabilitytoinhibitexpressionoftranscriptsthatincludedatruncatedhumanandrogenreceptorgenecontainingdifferentCAGrepeatlengths(16to112repeats)InmammaliancellssequencespecificsmalldsRNAsof22nucleotidesrescuedthetoxicityandcaspase3activationinducedbyplasmidsexpressingatranscriptencodinganexpandedpolyglutaminetractLiebermanetal(2002)showedthatthemouseMN1culturedcelllineexpressingthewildtypeandrogenreceptor(with24CAGrepeats)respondedtoligandbyshowingtrophiceffectsincludingprolongedsurvivalinlowserumwhereascellsexpressingthemutantreceptor(with65CAGrepeats)didnotshowarobusttrophicresponseThispartiallossoffunctioncorrelatedwithdecreasedlevelsofthemutantproteinduetoitspreferentialdegradationbytheubiquitinproteasomepathwayExpressionanalysisusingoligonucleotidearraysconfirmedthatthemutantreceptorunderwentapartiallossoffunctionandfailedtoregulateasubsetofgeneswhoseexpressionisnormallyaffectedbyligandactivationofthewildtypereceptorTheauthorsconcludedthatpolyglutamineexpansionaltersandrogenreceptorfunctionbypromotingitsdegradationandbymodifyingitsactivityasatranscriptionfactorExpressionofmisfoldedproteininculturedcellsfrequentlyleadstotheformationofjuxtanuclearinclusionsthathavebeentermed'aggresomes'Tayloretal(2003)showedthatmutantGFPtaggedandrogenreceptor(AR112Q)formedinsolubleaggregatesandwastoxictoculturedtransfectedcellsUsingmolecularandpharmacologicinterventionstodisruptaggresomeformationtheauthorsfoundthataggresomeformingproteinshadanacceleratedrateofturnoverwhichwasslowedbyinhibitionofaggresomeformationbecamemembraneboundandassociatedwithlysosomalstructuresTayloretal(2003)suggestedthataggresomesmaybecytoprotectiveandserveascytoplasmicrecruitmentcenterstofacilitatedegradationoftoxicproteinsInvitroSzebenyietal(2003)showedthatandrogenreceptorandhuntingtin(143100)polypeptidescontainingpathogenicpolyglutamine(polyQ)repeatsdirectlyinhibitedbothfastaxonaltransportandelongationofneuriticprocessesTheeffectsweregreaterwithtruncatedpolypeptidesandoccurredwithoutdetectablemorphologicaggregatesLaFevreBerntandEllerby(2003)foundthatexpressionofanexpandedARproteinwith112CAGrepeatsinhumankidneycellsactivated3MAPkinasepathwayscausingincreasedlevelsofphosphorylationofp44/42(601795)p38(600289)andSAPK/JNK(601158)Onlyinhibitionofthep44/42MAPkinasepathwayreducedcelldeathreducedthecleavageofexpandedARanddecreasedphosphorylationoftheexpandedARLaFevreBerntandEllerby(2003)postulatedthatphosphorylationatserine514oftheARproteinisrepeatlengthdependentandthatphosphorylationenhancestheabilityofcaspase3tocleaveARandgeneratetoxicpolyQfragmentsBuchananetal(2004)characterizedasomaticARgenemutationfromahumanprostatetumorthatresultedininterruptionofthepolyQtractby2nonconsecutiveleucineresidues(ARpolyQ2L)ComparedwithwildtypeARARpolyQ2Lexhibiteddisruptedinterdomaincommunication(N/Cinteraction)andalowerproteinlevelbutparadoxicallyhadmarkedlyincreasedtransactivationactivityMolecularmodelingandtheresponsetocofactorsindicatedthattheincreasedactivityofARpolyQ2LresultedfrompresentationofamorestableplatformfortherecruitmentofaccessoryproteinsthanwildtypeARAnalysisoftherelationshipbetweenpolyQtractlengthandARfunctionrevealedacriticalsize(16to29glutamines)formaintenanceofN/CinteractionSince91to99%ofARallelesindifferentracial/ethnicgroupsencodeapolyQtractintherangeof16to29glutaminesBuchananetal(2004)suggestedthatN/CinteractionmayhavebeenpreservedasanessentialcomponentofandrogeninducedARsignalingMAPPINGBysomaticcellhybridizationMigeonetal(1981)foundthattheandrogenreceptorlocusislocatedbetweenXq13andXp11andisproximaltothelocusforPGK(311800)ItmaybelocatedintheXq11regionjudgingbythefindingsin1rearrangementwithabreakthereLackofcomplementationwithcellsfromTfmofthemouseindicatedhomologyRearrangementmusthaveoccurredinevolutionhoweverbecausetheTfmlocusisnotnearthecentromereinthemouseFindingsconsistentwithlocalizationofthehumanTFMlocustoproximalXqnearthecentromerewerereportedbyWieackeretal(1985)whofoundacarrierwomanheterozygousforaRFLPofaprobecalledp8localizedbetweenXcenandXq134affectedchildrenhadinheritedthesamep8alleleIn2familieswithtesticularfeminizationand1familywithReifensteinsyndromeWieackeretal(1987)foundcloselinkage(indeednorecombination)betweenthediseasephenotypeandDNAmarkerDXS1Assumingthatthe2disordersareallelicthesummarizeddataledtoamaximumlodscoreof35attheta=00Lubahnetal(1988)clonedhumanARgenomicDNAfromaflowsortedhumanXchromosomelibrarybyusingaconsensusnucleotidesequencefromtheDNAbindingdomainofthefamilyofnuclearreceptorsTheylocalizedthegenetotheregionbetweenthecentromereandXq13bystudyinghumanrodenthybridsinwhichthehumanXchromosomewasfragmentedUsingaclonedcDNAforARBrownetal(1989)localizedtheARgenetoXq11q12byanalysisofsomaticcellhybridpanelssegregatingportionsoftheXchromosomeTheyalsofoundaRFLPthatshouldbeusefulinlinkageanalysisofvariousformsofinheritedandrogeninsensitivityInthemostextensivelyaffectedkindredknownwithcompleteandrogeninsensitivity(CAIS)onelivingintheDominicanRepublicImperatoMcGinleyetal(1990)foundlinkagetoDXS1andPGK1localizingtheARgenetoanareabetweenXq11andXq13LinkagebetweenDXS1andARshowedapeaklodscoreof32attheta=006NorecombinationwasfoundbetweenPGK1andARpeaklodscorewas29attheta=00AlthoughbothARandPGK1aredistaltoDXS1itwasnotpossibletodeterminethesequenceofthetwoUsing3cDNAprobesspanningvariouspartsoftheARgenetheycoulddemonstratenoabnormalityinrestrictionfragmentpatternssuggestingthatthegenedefectisnotadeletionbutratherapointmutationorasmallinsertion/deletionMOLECULARGENETICSPattersonetal(1994)describedadatabaseofARgenemutationswhichincluded114uniquemutationsGottliebetal(1996)describedthelatestversionoftheirARmutationdatabasewhichcontained212entriesrepresenting239patientswithandrogeninsensitivityorprostatecancer(176807)bearing155differentARmutationsGottliebetal(1997)statedthatthenumberofreportedmutationsintheirdatabasehadrisenfrom212to272TocomplementthedatabasetheyhadconstructedmutationmapsforAISphenotypesandforprostatecancerclassifiedthenumberandvarietyofmutationtypesandtabulatedinformationonthemultiplicityoftheCpGsitemutationsInanupdateontheARgenemutationdatabaseGottliebetal(2004)statedthatthereportedmutationshadrisenfrom374to605andthenumberofARinteractingproteinsdescribedhadincreasedfrom23to70overtheprevious3yearsInadditionsilentmutationshadbeenreportedinbothandrogeninsensitivitysyndromeandprostatecancercasesThedatabasealsoincorporatedinformationonspinobulbarmuscularatrophy(SBMA313200)whichiscausedbyaCAGrepeatinexon1oftheARgeneaswellasCAGrepeatlengthvariationsassociatedwithriskforbreastendometrialcolorectalandprostatecanceraswellasformaleinfertilityMooneyetal(2003)presentedamethodfordistinguishingdiseasecausingmutationsintheARgenefrommutationsthatareassociatedwithdiseasebuthavenocausalroleTheyusedameasureofnucleotideconservationamongsimilargenesaswellasARmutationspreviouslyidentifiedasdiseasecausinginvariousformsofAISandprostatecancerThedegreeofconservationofdiseasecausingmutationscorrelatedwiththeseverityoftheAISphenotypeandexperimentallyprovenprostatecancerlinkedmutationswerefoundtooccurinhighlyconservedregionsofthegeneStudiesontheARProteinWithanExpandedPolyglycineRepeatAndrogeneticalopecia(AGA109200)ormalepatternbaldnessisthemostcommonformofhairlossItspathogenesisisandrogendependentandgeneticpredispositionisthemajorrequirementforthephenotypeHillmeretal(2005)demonstratedthatgeneticvariationintheandrogenreceptorgeneisthecardinalprerequisiteforthedevelopmentofearlyonsetAGAwithanetiologicfractionof046TheinvestigationofalargenumberofgeneticvariantscoveringtheARlocussuggestedthatapolyglycineencodingGGNrepeatinexon1isaplausiblecandidateforconferringthefunctionaleffectTheXchromosomallocationofARstressedtheimportanceofthematernallineintheinheritanceofAGABecausepolymorphicCAG(polyglutamine)andGGN(polyglycine)segmentsregulateARfunctionAschimetal(2004)investigatediftherewasanassociationbetweenthesepolymorphismsandhypospadiasandcryptorchidismGenotypingwasperformedbydirectsequencingofDNAfrompatientsdiagnosedwithhypospadiasandcryptorchidismandcontrolsThesubjectswithhypospadiasweredividedintosubgroupsofglanularpenileandpenoscrotalhypospadiasMedianGGNlengthsweresignificantlyhigher(24vs23)amongsubjectswithcryptorchidismcomparedwithcontrols(P=0001)andthosewithpenilehypospadiascomparedwitheithercontrols(P=0003)orglanularandpenoscrotalhypospadiascombined(P=0018)ThefrequencyofcaseswithGGN24ormorevsGGN=23differedsignificantlyamongthosewithcryptorchidism(65/35%)comparedwithcontrols(31/54%)(P=0012)andamongsubjectswithpenilehypospadias(69/31%)comparedwitheithercontrols(P=0035)orglanularorpenoscrotalhypospadiascombined(32/55%)(P=0056)TherewerenosignificantdifferencesinCAGlengthsbetweenthecasesandcontrolsAndrogenInsensitivitySyndromeMcPhauletal(1992)analyzedthenucleotidesequenceoftheARgenefrom22unrelatedsubjectswithsubstitutionmutationsofthehormonebindingdomainElevenhadthephenotypeofcompletetesticularfeminization4hadincompletetesticularfeminizationand7hadReifensteinsyndromeThefunctionaldefectincludedabsenceofligandbindingin10subjectsandqualitativeorquantitativedefectsinbindingin10and2subjectsrespectivelyTheyobservedthatof19ofthe21substitutionmutations(90%)clusteredin2regionsthataccountforapproximately35%ofthehormonebindingdomainnamelybetweenaminoacids726and772andbetweenaminoacids826and864ThefactthatoneoftheseregionsishomologoustoaregionofthehumanthyroidhormonereceptorthatisaknownclustersiteformutationsthatcausethyroidhormoneresistanceimpliesthatthelocalizationofmutationsintheARgeneisnotcoincidenceInafamilyinwhich3membershadthecompleteformoftheandrogeninsensitivitysyndromeQuigleyetal(1992)foundcompletedeletionoftheARgeneinaffectedpersonsandshowedthatthemutationhadoriginatedinthegermlineofthematernalgreatgrandfatheroftheindexpatientQuigleyetal(1992)statedthatmutationanalysishadbeenperformedinatleast60unrelatedpersonsandthatinabouthalfadistinctsinglebasepairmutationhadbeenidentifiedthemutationproducedanalterationinaminoacidsequenceintroducingaprematureterminationcodonorinonecaseresultinginaberrantmRNAsplicing(RisStalpersetal1990)CompleteorpartialgenedeletionsappeartobeararemolecularcauseoftheandrogeninsensitivitysyndromeQuigleyetal(1992)pointedoutthattheaffectedindividualsintheirfamilyhadsparsefineblondvellushairoverthelabiamajoraandemphasizedthatthisshouldnotbereferredtoaspubichairThepubertaltransformationofvellushairintothelongercoarserdarkerterminalhaircharacteristicofadultpubicandaxillaryregionsisandrogendependentTheysuggestedthattheterm'sparsepubichair'beusedonlyinreferencetohairofthesamequalityasnormalandrogendependentterminalhairbutofdiminishedquantityandthatthetermcompleteandrogeninsensitivitysyndromebereservedforthosepatientswithcompleteabsenceoftruesexualhairMcPhauletal(1993)summarizedthespectrumofARgenemutationsin31unrelatedsubjectswithvariousformsofandrogenresistancesyndromeMostofthemutationswereduetonucleotidechangesthatcausedprematureterminationcodonsorsingleaminoacidsubstitutionswithintheopenreadingframeandmostofthesesubstitutionswerelocalizedin3regionsoftheandrogenreceptortheDNAbindingdomainand2segmentsoftheandrogenbindingdomainLessfrequentlypartialorcompletegenedeletionshadbeenidentifiedSultanetal(1993)tabulated45differentmutationsintheARgeneobservedinpatientswiththecompleteandrogeninsensitivitysyndromeand27mutationsfoundinpatientswithpartialandrogeninsensitivitysyndrome(PAIS)In5subjectsin4familieswithandrogeninsensitivityMuronoetal(1995)identifiedmutationsinthesteroidbindingdomainoftheandrogenreceptorFourofthesubjectsincluding2sibshadCAIS1subjectwithambiguousgenitaliahadamissensemutation(3137000008)Rodienetal(1996)reportedstrikingvariationsinthephenotypesof3relatedpatientswithamutationintheARgene(M780I3137000039)TwooftheaffectedfamilymembershadafemininephenotypewithTannerstage2pubichairsuggestingnearlycompleteandrogeninsensitivityThethirdsubjectwasmalewithperineoscrotalhypospadiasandcryptorchidismsuggestingreducedbutresidualandrogensensitivityGenitalskinfibroblastswereanalyzedfor5alphareductaseactivityandthebindingcapacityoftheandrogenreceptorwashigherinthemalethaninthe2patientswithfemalephenotypesThatthesamemutationindifferentaffected46XYmembersofthesamefamilycancausevariableclinicalphenotypessuggeststhattheARgenotypedoesnotaccuratelypredictthephenotypeinallfamilieswithandrogeninsensitivityJakubiczkaetal(1997)identifiedmutationsintheARgenein7of14patientsaffectedwithcompleteandrogeninsensitivityTheauthorsmadethefollowingconclusionsmajorstructuralabnormalitiessuchasdeletionshavebeenreportedinonlyafewcasesofCAISWhenbothDNAandsteroidbindingdomainsaredeletedcompleteandrogenresistanceresultsMinorstructuralabnormalitiessuchasdeletionsorinsertionsof1orafewnucleotidesarealsorareIfthereadingframeisdisturbedCAISresultsasisthecaseinthetesticularfeminizationmouseSinglebasemutationsarethemostcommontypeintheARgenePrematurestopcodonsoftheARgeneareusuallyassociatedwithcompleteandrogeninsensitivitysyndromeHolterhusetal(1997)identifiedanadultpatientwitha46XYkaryotypecarryingaprematurestopcodoninexon1oftheARgene(3137000042)whopresentedwithsignsofpartialvirilizationpubichairTannerstage4andclitoralenlargementNootherfamilymemberswereaffectedExaminationofthesequencinggelidentifiedawildtypealleleindicatingmosaicismInadditioneliminationoftheuniqueAftIIrecognitionsiteinducedbythemutationwasincompletethusconfirmingmosaicismNormalandrogenbindingstudiesdemonstratedexpressionofthewildtypeARinthepatient'sgenitalskinfibroblastsHolterhusetal(1997)concludedthatsomaticmosaicismoftheARgeneshiftsthephenotypetoahigherdegreeofvirilizationthanexpectedfromthegenotypeofthemutantallelealoneMcPhauletal(1997)usedarecombinantadenovirustodeliveranandrogenresponsivegeneinfibroblastculturesinordertoassayARfunctioninnormalsubjectsandpatientswithdifferentformsofandrogenresistanceTheystudied3groupsofpatientswithknownorsuspecteddefectsinARfunctionincludingthosewithReifensteinsyndromespinobulbarmuscularatrophyandsevereformsofisolatedhypospadiasWhenassayedusingthismethodtheARfunctionofpatientswithReifensteinsyndromewasintermediatebetweenthatofnormalcontrolsandthatofpatientswithcompletetesticularfeminizationTheauthorsconcludedthatdefectiveARfunctioncanbedetectedinfibroblastsestablishedfrompatientswithspinobulbarmuscularatrophyandinsomepatientswithsevereformsofisolatedhypospadiasincluding2withanormalARgenesequenceHiortetal(1998)demonstratedthatdenovoandinparticularsomaticnewmutationsoccuratanunexpectedlyhighrateinAISIntheARgenemutationdatabasemaintainedinMontrealGottliebetal(2001)found25caseswheredifferentdegreesofandrogeninsensitivitywerecausedbyidenticalmutationsintheARgeneIn5ofthesecasesthephenotypicvariabilitywasduetosomaticmosaicismthatissomaticmutationsthatoccurredinonlycertaincellsofandrogensensitivetissueHolterhusetal(1999)reporteda46XYnewbornwithambiguousgenitaliaandmutationintheARgene(3137000005)DirectDNAsequencingandonlyincompleteNlaIIIdigestionofagenomicDNA/PCRfragmentcontainingthemutationdisplayedthecoexistenceofmutantandwildtypeandrogenreceptorallelesBecausethepatientwastheonlyaffectedfamilymemberandbecauseonlythewildtypeandrogenreceptorDNAsequencewaspresentinthemotherHolterhusetal(1999)concludedthatthemutationhadoccurreddenovoatthepostzygoticstageleadingtosomaticmosaicismAnalysisofmethyltrienolonebindingonthepatient'sculturedgenitalskinfibroblastsrevealedtheexpressionof2functionallydifferentandrogenreceptorsThisfindingconfirmedsomaticmosaicisminthepatientandindicatedthatthemostlikelymolecularmechanismresponsiblefortheunexpectedlystrongvirilizationoftheprobandistheandrogenactionthroughthewildtypeARexpressedbypartofthesomaticcellsHolterhusetal(1999)presentedtheclinicalandmolecularspectrumofsomaticmosaicismin5patientsTheysuggestedthatfunctionallyrelevantexpressionofthewildtypeandrogenreceptorneedstobeconsideredinallmosaicindividualsandthattreatmentshouldbeadjustedaccordinglyHolterhusetal(2000)reportedafamilywith4affectedindividuals3brothersandtheiruncledisplayingstrikinglydifferentexternalgenitaliaTheydetectedthesameleu712tophe(L712F3137000050)ARmutationineachsubjectTheydemonstratedthatthe712FARcouldswitchitsfunctionfromsubnormaltonormalwithinthephysiologicconcentrationrangeoftestosteroneTheauthorsconcludedthattakingintoaccountthewelldocumentedindividualandtimedependentvariationintestosteroneconcentrationinearlyfetaldevelopmenttheirobservationsillustratedthepotentialimpactofvaryingligandconcentrationsfordistinctcasesofphenotypicvariabilityinAISMcPhaulandGriffin(1999)reviewedthespectrumofARdefectsthatcausemalephenotypicabnormalitiesaswellastheclinicalcharacteristicsoftheheterogeneousARmutationsincludingtheireffectsonARproteinstructureandtheirfrequenciesandgenelocationsPoujoletal(2002)integratedclinicalmolecularandstructuraldatainaninvestigationintothecharacteristicsofARligandbindingandactivationTheylookedforresiduessubstitutedinAISthatareconservedamongthedifferentARspeciesbutthatdivergeintheothersteroidreceptorsthussuggestingaroleinandrogenbindingspecificityOftheresiduesfittingthesecharacteristicstheyfocusedontheglycineatposition743forwhichthenaturalsubstitutionsglutamicacid(G743E3137000057)andvaline(G743V3137000056)havebeenassociatedwithdifferentandrogenresistancephenotypesTheconsequencesofbothsubstitutionswereevaluatedalongwiththoseofamanufacturedminimalglycinetoalaninemutationThegradualimpairmentofbindingandtransactivationefficienciesinARmutantsrangingfromalaninetovalineandsubsequentlyglutamicacidwerehighlightedbyinvitroexperimentsStructuralanalysesshowedtheconsequencesofthesesubstitutionsattheatomiclevelandsuggestedadifferenceinlocalorganizationamongthenuclearreceptorsuperfamilyTheauthorsconcludedthatthisintegrativeapproachprovidesausefultoolforfurtherinvestigationsintotheARstructurefunctionrelationshipinAISXuetal(2003)describeda3montholdgirlwithCAISinwhomthediagnosiswasmadeduringelectiverepairofinguinalherniawhichhadbeennotedshortlyafterbirthShehada46XYkaryotypewithinversionoftheXchromosomewithonebreakdisruptingtheARgeneCuriouslythephenotypicallynormalmotheralsocarriedtheinversioninoneXchromosomeamaternalaunthadCAISanda46inv(X)YkaryotypeAttheageof5yearsthisaunthadundergonerepairofinguinalherniasatwhichtimetesteswereidentifiedSheunderwentgonadectomy1yearlaterbecauseofconcernsofpotentialmalignancyAtage16yearsshehadprimaryamenorrheaandaheightof180cmMeloetal(2003)studied32subjectswithmalepseudohermaphroditismduetoandrogeninsensitivitysyndromefrom20families9withCAISand11withPAISTheyanalyzedtheentirecodingregionoftheandrogenreceptorgeneandfoundmutationsinallfamilieswithCAISandin8ofthe11familieswithPAISTheyidentified15differentmutationsincluding5thathadnotbeendescribedTheycompareddetailedclinicalandhormonalfeatureswithgenotypein25subjectswithAISandconfirmedthesebymutationanalysisPitteloudetal(2004)reporteda61yearoldmanwithandrogeninsensitivityandcoincidentalfunctionalhypogonadotropichypogonadismWhilefunctionalhypogonadotropichypogonadismisnotawellrecognizedentityinmalesmajorstresshasbeenreportedtocausetransientsuppressionofthehypothalamicpituitarygonadalaxisinmenThepatientwasnotedtohaveundervirilizationminimalpubertaldevelopmenthypogonadaltestosteroneandlowgonadotropinlevelsconsistentwithcongenitalhypogonadotropichypogonadismduringahospitaladmissionformyocardialinfarctionThepatientwasfoundtohavePAISduetoaser740tocysmutation(3137000059)intheligandbindingdomainoftheARSubsequentstudiesconfirmedthathehadthecharacteristicgonadotropinandsexsteroidabnormalitiesofPAISTheauthorsconcludedthatthiswasthefirstreportedcaseofPAISpresentingwithareversiblehypogonadotropicbiochemicalprofiletriggeredbyanacuteillnessandcorticosteroidtherapyKohleretal(2005)notedthatin70%ofAIScasesARmutationsaretransmittedinanXlinkedrecessivemannerthroughthecarriermothersbutin30%themutationsarisedenovoWhendenovomutationsoccurafterthezygoticstagetheyresultinsomaticmosaicismswhichareanimportantconsiderationforbothvirilizationinlaterlifebecausebothmutantandwildtypereceptorsareexpressedandgeneticcounselingTheauthorsreported6patientswithAISduetosomaticmutationsoftheARand1motherwithsomaticmosaicismwhotransmittedthemutationtwiceOfthe4patientswithPAIS3presentedspontaneousorinducedvirilizationatbirthorpubertyThesecasesunderlinethecrucialroleoftheremnantwildtypeARforvirilizationbecausethesamemutationswhentheyareinheritedleadtoCAISTheyalsoreported2novelmutationsoftheARwithsomaticmosaicismdetectedinpatientswithCAISThustheremnantwildtypereceptordoesnotalwaysleadtovirilizationWhenagermlinedenovoARmutationisidentifiedintheindexcasetheriskoftransmissiontoasecondchildduetoapossiblegermcellmosaicisminthemothercannotbeexcludedHowevergiventhehighnumberofARdenovomutationsandtherarityofsuchreportsthisriskappearstobeverylowSpinalandBulbarMuscularAtrophyLaSpadaandFischbeck(1991)andLaSpadaetal(1991)presentedevidencethatXlinkedspinalandbulbarmuscularatrophyisduetoamutationinthepolyglutaminetractencodedbythefirstexonoftheARgene(3137000014)ThemutationsconsistedofincreasedsizeofapolymorphictandemCAGrepeatinthecodingregionTheseamplifiedrepeatswereabsolutelyassociatedwiththedisorderbeingpresentin35unrelatedpatientsandnoneof75controlsTheysegregatedwiththediseasein15familieswithnorecombinationin61meiosesmaximumlodscore=132attheta=0ElevendifferentdiseasealleleswereobservedindicatingthattheassociationwasnotlikelytorepresentlinkagedisequilibriumAsreviewedbyGriffin(1992)the'clinicalspectrum'ofandrogenresistancealreadyincludedinfertilemalesyndromeandundervirilizedmalesyndromethenewfindingextendedthespectrumCaskeyetal(1992)reviewedtripletrepeatmutationsidentifiedin2ofthemostcommonheritabledisordersfragileXsyndrome(300624)andmyotonicdystrophy(160900)andinSBMAOthersimilaritiestothefragileXsyndromeandmyotonicdystrophywerepointedoutbyBiancalanaetal(1992)inafamilywithaffectedmembersin4generationsthemutantallelewasunstableupontransmissionfromparenttochildwithadocumentedvariationfrom46to53CAGrepeatsandatendencytoincreaseinsize(7increasesandasingledecreasein17events)whichappearedstrongerupontransmissionfromamalethanfromafemaleTherewasalsoevidenceforlimitedsomaticinstabilityoftheabnormalallelewithobservablevariationofupto2to3repeatsProstateCancerIn1of26specimensofuntreatedorganconfinedstageBprostatecancerNewmarketal(1992)identifiedasomaticmutationintheARgene(3137000013)inahighlyconservedregionwithinthehormonebindingdomainAnabundanceofthemutatedfragmentindicateditspresenceincellswithagrowthadvantageTheauthorspostulatedthatsomaticmutationintheARgeneleadingtopersistentexpressioncouldgiverisetoandrogenindependentprostatecancerThelengthofapolymorphicCAGrepeatsequenceoccurringintheandrogenreceptorgeneisinverselycorrelatedwithtranscriptionalactivitybytheandrogenreceptorMenwhopossessexceptionallylongCAGrepeatlengthsexperienceclinicalandrogeninsensitivitypresumablyrelatedtoreducedtranscriptionalactivityofthereceptorProstatecarcinogenesisisdependentonandrogensBecauseshorterCAGrepeatlengthsareassociatedwithhightranscriptionalactivityofARIrvineetal(1995)proposedthatmenwithshorterrepeatlengthswillbeathigherriskforprostatecancerSomeindirectevidenceisconsistentwiththishypothesisAfricanAmericanswhohavegenerallyshorterCAGrepeatlengthsintheARgenehaveahigherincidenceandmortalityratefromprostatecancer(CoetzeeandRoss1994)MoreoverbecauseofXlinkageahistoryofdiseaseinabrothercarriesgreaterriskthanpaternalhistoryAgainstthisbackgroundGiovannuccietal(1997)conductedwithinthePhysician'sHealthStudyanestedcasecontrolledstudyof587newlydiagnosedcasesofprostatecancerdetectedbetween1982and1995and588controlswithoutprostatecancerTheyfoundanassociationbetweenfewerandrogenreceptorgeneCAGrepeatsandhigherriskoftotalprostatecancerInparticularashorterCAGrepeatsequencewasassociatedwithcancerscharacterizedbyextraprostaticextensiondistantmetastasesorhighhistologicgradeVariabilityintheCAGrepeatlengthwasnotassociatedwithlowgradeorlowstagediseaseTotestforanassociationbetweenclinicalparametersofhumanprostatecancerandCAGrepeatlengthHardyetal(1996)analyzednormallymphocyteDNAfrom109patientsThemedianageofpatientswas63years(range42to83)with104Caucasian2AfricanAmerican1Asianand2ofotherracialoriginThemedianrepeatlengthwas252222and23forpatientspresentingwithstageABCandDdiseaserespectivelyAsignificantcorrelationbetweenCAGrepeatlengthandageatonsetwasobservedwhereascorrelationswithstagelevelofprostatespecificantigenatdiagnosisandtimetoprostatespecificantigenrelapsewerenotsignificantShorterCAGrepeatlengthsmaybeassociatedwiththedevelopmentofprostatecancerinmenatayoungerageChangetal(2002)foundsignificantlyincreasedfrequenciesofARallelescarrying16orlessGGCrepeatsin159independenthereditaryprostatecancercases(71%)and245sporadicprostatecancercases(68%)comparedwith211controls(59%)NoevidenceforassociationbetweenCAGrepeatsandprostatecancerriskwasobservedSimilarresultswerefoundwithatestforlinkagebyparametricanalysisandthemalelimitedXlinkedtransmission/disequilibriumtestOtherMaleSpecificPhenotypesAssociatedWithExpandedPolyglutamineRepeatintheARGeneMackeetal(1993)used3complementaryapproachestotestthehypothesisthatsequencevariationintheARgeneplaysacausalroleinthedevelopmentofmalesexualorientationlinkageanalysisusingpairsofhomosexualbrothersmeasurementofrepeatlengthsintractsofsingleaminoacidsthatareknowntobehighlyvariableinthepopulationanddirectscreeningfornucleotidesequencechangesTheanalysesshowedthathomosexualbrothersareaslikelytobediscordantasconcordantforandrogenreceptorallelestherearenolargescaledifferencesbetweenthedistributionsofpolyglycineorpolyglutaminetractlengthsinthehomosexualandcontrolgroupsandcodingregionsequencevariationisnotcommonlyfoundwithintheandrogenreceptorgeneofhomosexualmenThedenaturinggradientgelelectrophoresis(DGGE)screenidentified2rareaminoacidsubstitutionsser205toargandglu793toaspthebiologicsignificanceofwhichwasunknownZhangetal(1994)studiedtheinstabilityofCAGtrinucleotiderepeatsinthehumanARgenebytypingapproximately4300humanspermWhilethemutationratefor20to22repeatalleleswassimilartothatshownbyfamilyanalysisalleleswith28to31repeatshada44timesgreaterrateofmutationwithcontractionsoutnumberingexpansions9to1Theauthorssuggestedthatdiseasecausingallelesmaybesusceptibleto2differentmutationalmechanismsoneprimarilyresultingincontractionandanotherleadingtotrinucleotideexpansionTutetal(1997)hypothesizedthatchangesintheARgenecouldhavearoleinsomecasesofmaleinfertilityassociatedwithimpairedspermatogenesisTotestthishypothesistheyexaminedthelengthsofthepolyglutamineandpolyglycinerepeatsin153patientswithdefectivespermproductionandcomparedthemtothoseof72normalcontrolsofprovenfertilityTherewasnosignificantassociationbetweenthepolyglycinetractandinfertilityHoweverpatientswith28ormoreglutaminesintheirARhadagreaterthan4fold(95%CI49to32)increasedriskofimpairedspermatogenesisandthemoreseverethespermatogenicdefectthehighertheproportionofpatientswithalongerGlnrepeatTheriskofdefectivespermatogenesiswashalvedwhenthepolyglutaminetractwasshort(23orlessglutamines)WholecelltransfectionexperimentsusingARconstructsharboring1520or31GlnrepeatsandaluciferasereportergenewithanandrogenresponseelementpromoterconfirmedaninverserelationshipbetweenGlnnumberandtransregulatoryactivityImmunoblotanalysesindicatedthatthereducedandrogenicityoftheARswithlongerGlnrepeatswasunlikelytobeduetoachangeinARproteinlevelsTheauthorsconcludedthatthereisadirectrelationbetweenthelengthoftheARpolyglutaminetractandtheriskofdefectivespermatogenesisthatisattributabletothedecreasedARfunctionalcompetencethatoccurswithlongerGlntractsDowsingetal(1999)characterizedtheandrogengenein35malepatientswithinfertilityThirtyhadidiopathicazoospermiaoroligozoospermiaandthesemenwerefoundtohavesignificantlylongerCAGrepeattractsthancontrols(mean232vs205p=00001)TheoddsofhavingCAGrepeatlengthsof20were6foldhigherforfertilementhanformenwithaspermatogenicdisorderKooyetal(1999)reported3brotherswithmentalretardationbehaviorproblemsmarfanoidhabitusandnormalmalegenitaliawhohadacontractedCAGrepeatintheirARgenes(8repeatscomparedtothe11to33repeatsnormallyseen)TheauthorsconcludedthatacausativerelationshipbetweenashortCAGrepeatintheARgeneandtheobservedphenotypecouldnotbeexcludedLimetal(2000)examinedwhetherlongerAR(Gln)nrepeatsareassociatedwithmoderatetosevereundermasculinizationClinicalfeaturesamongthe78undermasculinized46XYmalesstudiedincludedpartlyfusedorunfusedscrotummicropenisandhypospadiasTheaverageAR(Gln)nlengthoftheundermasculinizedgroup(median25interquartilerange2326)wassignificantlygreaterthanthatofthe850controls(median23interquartilerange2226p=0002)Theoddsratioofhaving23ormorerepeats(asopposedto22orfewerrepeats)intheundermasculinizedgroupwas251(95%CI141448)Theestimatedincreaseintheoddsratioforeachadditionalrepeatwas907%TheauthorshypothesizedthattheassociationofundermasculinizedgenitaliaandisolatedmalefactorinfertilitywithAR(Gln)nlengthprovidedfurtherevidencethattheymayrepresentdifferentdegreesofseverityofthesamediseaseprocessThefactthatspermnumbersrangefrom20to300million/mLinnormalmenwithoutanyindicationofchangedendocrineparametersledvonEckardsteinetal(2001)toassumethatgeneticvariabilityoftransductionofandrogensignalingcouldbeimportantTheycomparedthevariablenumberofCAGrepeatsintheARwithspermconcentrationsinmenwithnormalejaculateparameters(62fathersand69volunteersparticipatinginclinicaltrials)InmultivariateanalysisCAGrepeatlengthdidnotdifferbetweenthevolunteersandthefathersbutwassignificantlycorrelatedtospermconcentrationswithacoefficientof025Whencomparedwithagroupofinfertilemen14withand30withoutafamilyhistoryofinfertilitynosuchcorrelationwasfoundTheauthorsconcludedthatmenwithshortCAGrepeatshavethehighestspermoutputwithinthenormalfertilepopulationandthatARpolymorphismscontributetotheefficiencyofspermatogenesisinnormalmenbutdonotplayapredominantroleinmaleinfertilityZitzmannetal(2001)investigatedtheinteractionsamongtheCAGpolymorphismserumlevelsofsexhormonescardiovascularriskfactorsandflowmediatedandnitrateinducedvasodilatationofthebrachialarteryin110healthymalesaged25to50yearsThenumberofCAGrepeatshadnosignificantcorrelationswithserumconcentrationsoftotalorfreetestosteroneStepwisemultipleregressionanalysisrevealedpositivecorrelationsofthenumberofCAGrepeatswithserumlevelsofhighdensitylipoprotein(HDL)cholesterolandflowmediatedvasodilatationTheassociationofCAGrepeatswithHDLcholesterolwasindependentofbodyfatcontentandserumlevelsoffreetestosteronebothofwhichhadsignificantnegativecorrelationswithHDLcholesterolTheauthorsconcludedthatalownumberofCAGrepeatsintheARgeneimpliesagreaterchanceforlowlevelsofHDLcholesterolandreducedendothelialresponsetoischemiawhichareimportantriskfactorsforcoronaryheartdiseaseZitzmannetal(2003)investigatedtheeffectofARCAG(n)repeatlengthonprostatevolumeandgrowthintestosteronesubstitutedhypogonadalmen69withprimaryhypogonadismand62withsecondaryhypogonadismAverageprostatesizeincreasedfrom158+/61mlto230+/68mlANOVAincludingcovariatesrevealedinitialprostatesizetobedependentonageandbaselinetestosteronelevelsbutnotonnumberof(CAG)nProstategrowthperyearandabsoluteprostatesizeundersubstitutedtestosteronelevelswerestronglydependenton(CAG)nwithlowertreatmenteffectsinlongerrepeatsTheoddsratioformenwithfewerthan20(CAG)ncomparedwiththosewith20ormore(CAG)ntodevelopaprostatesizeofatleast30mlundertestosteronesubstitutionwas87(95%CI31243plessthan0001)Thisobservationwasstronglyagedependentwithamorepronouncedoddsratioinmenolderthan40yearsTheauthorsconcludedthatthisfirstpharmacogeneticstudyonandrogensubstitutioninhypogonadalmendemonstratedamarkedinfluenceoftheARgene(CAG)npolymorphismonprostategrowthZitzmannetal(2004)analyzedphenotypicandclinicaltraitsin77newlydiagnosedanduntreatedpatientswithKlinefeltersyndromeanda47XXYkaryotypeinregardtotheputativeinfluenceofXchromosomeinactivationandAR(CAG)nlengthIn48menwhowerehypogonadalandreceivedTsubstitutiontherapypharmacogeneticeffectswereinvestigatedTheshorter(CAG)nallelewaspreferentiallyinactive(CAG)nlengthwaspositivelyassociatedwithbodyheightBonedensityandtherelationofarmspantobodyheightwereinverselyrelatedto(CAG)nlengthThepresenceoflong(CAG)nwaspredictiveforgynecomastiaandsmallertesteswhereasshort(CAG)nwereassociatedwithastablepartnershipandprofessionsrequiringhigherstandardsofeducationalsowhencorrectedforfamilybackgroundTherewasatrendformenwithlonger(CAG)ntobediagnosedearlierinlifeUndertestosteronesubstitutionmenwithshorter(CAG)nexhibitedamoreprofoundsuppressionofluteinizinghormone(LHsee152780)levelsaugmentedprostategrowthandhigherhemoglobinconcentrationsTheeffectsoftestosteronesubstitutionarepharmacogeneticallymodifiedandthisfindingismagnifiedbypreferentialinactivationofthemorefunctionalshort(CAG)nalleleZinnetal(2005)investigatedtheroleoftheARCAG(n)repeatlengthtophenotypicvariabilityinKlinefeltersyndromeTheCAG(n)repeatlengthwasinverselycorrelatedwithpenilelengthabiologicindicatorofearlyandrogenactionMosaicismimprintingandskewedXinactivationdidnotaccountforthevariabilityoftheKlinefeltersyndromephenotypeZinnetal(2005)concludedthatnormalgeneticvariationintheARcodingsequencemaybeclinicallysignificantinthesettingofearlytesticularfailureandsubnormalcirculatingtestosteronelevelsasoccursinKlinefeltersyndromeAssociationWithFemaleSpecificPhenotypesCalvoetal(2000)foundnoassociationbetweentheARCAGrepeatnumberandhirsutisminwomenwithorwithouthyperandrogenemiaSkewedXchromosomeinactivationwasfoundin10(149%)of67subjects(3withidiopathichirsutism5withhyperandrogenichirsutismand2controlsp=0746)whichwasnotsignificantToinvestigatetheroleoftheARCAGrepeattractinpolycysticovariansyndrome(PCOS184700)Mifsudetal(2000)measureditslengthin91patientswithultrasounddiagnosisofpolycysticovariesirregularmenstrualcyclesandanovulatoryinfertilityandcomparedthemto112controlsubjectsofprovenfertilitywithregularmensesTheycompareddifferencesinCAGlengthbetweenpatientswhoseserumtestosteronelevelswerebelowthenormallaboratorymeantothosethatwerehigherTherewasatrendforalowermeanCAGbialleliclengthamonganovulatorypatientswithserumtestosteronelessthan173nmol/Lcomparedwiththosewhosetestosteronewasmorethan173nmol/LThisdifferenceinCAGlengthbetweenpatientswithlowandhightestosteronelevelswashighlysignificantwhenonlytheshorteralleleofeachindividualwasconsideredEthnicdifferenceswerealsoevidentinthedataIndiansubjectshadasignificantlyshorterARCAGlengthcomparedwithChineseTheauthorsconcludedthattheirdataindicatedanassociationbetweenshortCAGrepeatlengthandthesubsetofanovulatorypatientswithlowserumandrogenssuggestingthatthepathogenicmechanismsofpolycysticovariesinthesepatientscouldbeduetotheincreasedintrinsicandrogenicactivityassociatedwithshortARallelesHickeyetal(2002)comparedfrequencydistributionofCAGrepeatallelesandtheirpatternofexpressionviaXinactivationanalysisamong83fertilewomenand122infertilewomenwithPCOSallofAustralianCaucasianethnicityApopulationcomparisonwith831predominantlyfertileAustralianwomenwasalsousedInfertilewomenwithPCOSexhibitedagreaterfrequencyofCAGallelesorbiallelicmeansgreaterthan22repeatscomparedwithboththefertilecontrolgroup(plessthan005)andthegeneralpopulation(plessthan001)PreferentialexpressionoflongerCAGrepeatalleleswasalsoobservedinPCOSandcorrelatedwithincreasedserumTTheauthorsconcludedthattheAR(CAG)ngenelocusand/oritsdifferentialmethylationpatternsinfluencethediseaseprocessleadingtoPCOSToelucidatethepossibleroleofgeneticvariationinARESR1(133430)andESR2(601663)onserumandrogenlevelsinpremenopausalwomenWestbergetal(2001)studiedtheCAGrepeatpolymorphismoftheARgenetheTArepeatpolymorphismoftheESR1geneandtheCArepeatpolymorphismoftheESR2geneinapopulationbasedcohortof270womenWomenwithrelativelyfewCAGrepeatsintheARgeneresultinginhighertranscriptionalactivityofthereceptordisplayedhigherlevelsofserumandrogensbutlowerlevelsofLH(see152780)thanwomenwithlongerCAGrepeatsequencesTheCArepeatoftheESR2genealsowasassociatedwithandrogenandsexsteroidhormonebindingglobulin(SHBG182205)levelswomenwithrelativelyshortrepeatregionshencedisplayedhigherhormonelevelsandlowerSHBGlevelsthanthosewithmanyCArepeatsIncontrasttheTArepeatoftheESR1genewasnotassociatedwiththelevelsofanyofthehormonesmeasuredTheauthorsconcludedthatserumlevelsofandrogensinpremenopausalwomenmaybeinfluencedbyvariantsoftheARgeneandtheESR2geneInastudyof255Canadianwomenwithbreastcancer(114480)and461controlsGiguereetal(2001)foundthatthosewithanARCAGrepeatlengthof39orlesshadasignificantlydecreasedriskfordiseasedevelopment(oddsratioof05)comparedtowomenwithCAGrepeatlengthsgreaterthan40Theassociationwasstrongerinpostmenopausalwomen(oddsratioof03)Giguereetal(2001)concludedthatshortallelesoftheCAGrepeatwereprotectiveagainstbreastcancerandsuggestedthattheprotectionwastheconsequenceofincreasedresponseandsensitivitytoandrogenswhichmayinhibitthegrowthofbreastcancercellsTotestthehypothesisthatriskforthedevelopmentofprecociouspubarcheandsubsequentfeaturesofovarianhyperandrogenismmightrelatetogeneticvariationinandrogenreceptorsensitivityIbanezetal(2003)comparedCAGrepeatnumberinBarcelonaSpanishgirlswhopresentedwithprecociouspubarcheagainstSpanishcontrolsandexaminedtherelationshipbetweenCAGnumberandclinicalmetabolicphenotypesofovarianhyperandrogenismpostmenarcheGirlswithprecociouspubarchehadshortermeanCAGnumberthancontrols(PPvscontrolsmeanrange213731repeatsvs2201532p=0003)andgreaterproportionofshortallelesof20repeatsorless(370%vs246%p=0002)AmongpostmenarchealgirlswithprecociouspubarcheshorterCAGnumberwasassociatedwithhigher17hydroxyprogesteronelevelsinresponsetoaGNRH(152760)agonistindicativeofovarianhyperandrogenismhighertestosteronelevelsacneandhirsutismscoresandmoremenstrualcycleirregularitiesTheauthorsconcludedshorterARgeneCAGnumberindicativeofincreasedandrogensensitivityincreasesriskforprecociouspubarcheandsubsequentovarianhyperandrogenismToassesswhetherabnormalitiesinARfunctioninbothperipheralbloodleukocytes(PBLs)andandrogentargettissuesarepresentinchildrenwithprematurepubarcheVotteroetal(2006)studied25girlswithPP23prepubertalchildrenand20girlswithTannerstageIIpubertaldevelopmentInPBLsfromPPpatientsARgenemethylationwassignificantlylower(plessthan001)thanthatofprepubertalchildrenandsimilartothatofgirlswithTannerIIstagepubertaldevelopmentAnegativecorrelationbetweenARgenemethylationinPBLsandtheageofnormalchildrenwasdetectedThemeannumberofCAGrepeatswaslowerinPPpatientsthaninprepuberalandTannerstagegirlsalthoughitwaswithinthenormalrangeforthegeneralpopulationinbothgroupsVotteroetal(2006)concludedthattheincreasedARactivityobservedinPPpatientsasindicatedbythereducedARgenemethylationpatterntogetherwiththepresenceofshorterCAGrepeatsmightleadtohypersensitivityofthehairfolliclestosteroidhormonesandthereforetotheprematuredevelopmentofpubichairAssociationWithOsteoarthritisInacasecontrolcohortof158Greekpatientswithidiopathicosteoarthritisoftheknees(see165720)and193controlsFytilietal(2005)studiedlong(L)andshort(S)allelesofthe1174(TA)n1092+3607(CA)nand172(CAG)nrepeatpolymorphismsoftheESR1ESR2andandrogenreceptorgenesrespectivelyWhenoddsratioswereadjustedforvariousriskfactorsitwasobservedthatwomenwithLLgenotypesforESR2andARgenesshowedsignificantlyincreasedriskforthedevelopmentofosteoarthritis(p=0002and0001respectively)POPULATIONGENETICSEdwardsetal(1992)demonstratedthatthedistributionofthenumberofCAGrepeatsinexon1oftheARgenewaslowestinAfricanAmericansintermediateinnonHispanicwhitesandhighestinAsiansThedistributionofallelesizewasbimodalinAfricanAmericansandonlyinAfricanAmericanswasthereadeviationfromHardyWeinbergequilibriumIrvineetal(1995)studiedthedistributionoftheCAGandGCmicrosatelliterepeatsinexon1oftheARgeneinAfricanAmericansnonHispanicwhitesandAsians(JapaneseandChinese)andconfirmedthefindingsofEdwardsetal(1992)Thefrequencyofprostatecancer(176807)inthe3racialgroupsisinverselyproportionaltothelengthoftherepeatsOneofthecriticalfunctionsoftheproductoftheARgeneistoactivatetheexpressionoftargetgenesThistransactivationactivityresidesintheNterminaldomainoftheproteinencodedinexon1whichcontainsthepolymorphicrepeatsThesmallersizeoftheCAGrepeatisassociatedwithahigherlevelofreceptortransactivationfunctiontherebypossiblyresultinginahigherriskofprostatecancerIrvineetal(1995)notedthatSchoenbergetal(1994)hadobservedasomaticmutationresultinginacontractionoftheCAGrepeatfrom24to18inanadenocarcinomaoftheprostateandthattheeffectsoftheshorterallelewereimplicatedinthedevelopmentofthetumorIntheFrenchandGermanpopulationsCorreaCerroetal(1999)foundnoassociationbetweentheriskofprostatecancerandallelesoftheCAGandGGCrepeatsinthefirstexonoftheARgeneKittlesetal(2001)presenteddataonCAGandGGCallelicvariationandlinkagedisequilibriumin6diversepopulationsfromAfricaAsiaandNorthAmericaPopulationsofAfricandescentpossessedsignificantlyshorterallelesforthe2locithannonAfricanpopulations(plessthan00001)AllelicdiversityforbothmarkerswashigheramongAfricanAmericansthananyotherpopulationincludingindigenousAfricansfromSierraLeoneandNigeriaApproximately20%ofCAGandGGCrepeatvariancewasattributedtodifferencesbetweenpopulationsAllnonAfricanpopulationspossessedthesamecommonhaplotypewhereasthe3populationsofAfricandescentpossessed3divergentcommonhaplotypesSignificantlinkagedisequilibriumwasobservedinthesampleofhealthyAfricanAmericansMifsudetal(2000)foundthattheaveragebiallelicmeanCAGlengthinChinesesubjects(patientsandcontrols)waslongerthanforIndiansbeing2316+/017and2208+/05respectively(p=0035)Themeanlengthoftheshortallelewasalsodifferentbetweenthe2groupsANIMALMODELAnimalModelofSpinalandBulbarMuscularAtrophyLaSpadaetal(1998)attemptedtomodeldiseasepathogenesisandrepeatinstabilityattheSBMA(313200)locusbycreatingtransgenicmouselineswithyeastartificialchromosomescarryingCAGrepeatexpansionsinthehumanARgeneTransgenicmicewith(CAG)45allelesshowedanapproximately10%rateofrepeatlengthinstabilityintransgenepositiveprogenyThe(CAG)45repeattractwassignificantlymoreunstablewithmaternaltransmissionandasthetransmittingfemaleagedAsegmentofabout70kboftheARlocusappearedtocontainacisactinginstabilityelementAbeletal(2001)createdtransgenicmicethatdevelopedmanyofthemotorsymptomsofSBMAandhadatruncatedhighlyexpandedARgenedrivenbytheneurofilamentlightchain(162280)promoterInadditiontransgenicmicecreatedwiththeprionprotein(176640)promoterdevelopedwidespreadneurologicdiseasereminiscentofjuvenileformsofotherpolyglutaminediseasesThedistributionofneurologicsymptomsdependedontheexpressionlevelandpatternofthepromoterusedratherthanonspecificcharacteristicsofandrogenreceptormetabolismorfunctionThetransgenicmicethatweregenerateddevelopedneuronalintranuclearinclusions(NIIs)ahallmarkofSBMAandtheotherpolyglutaminediseasesTheseinclusionswereubiquitinatedandsequesteredmolecularchaperonescomponentsofthe26Sproteasome(604449)andthetranscriptionalactivatorCREBbindingprotein(CBP600140)ApartfromthepresenceofNIIsevidenceofneuropathologyorneurogenicmuscleatrophywasabsentsuggestingtotheauthorsthattheneurologicphenotypesobservedweretheresultofneuronaldysfunctionratherthanneuronaldegenerationSimilarfindingswerereportedbyAdachietal(2001)whogeneratedtransgenicmicethatexpressedahighlyexpanded239polyglutamine(polyQ)repeatunderthecontrolofthehumanARpromoterTheauthorsconcludedthatpolyQalonecaninducetheneuronaldysfunctionthatprecedesgrossneuronaldegenerationMcManamnyetal(2002)developedatransgenicmodelofSBMAexpressingafulllengthhumanARcDNAcarrying65(AR65)or120CAGrepeats(AR120)withwidespreadexpressiondrivenbythecytomegaloviruspromoterMicecarryingtheAR120transgenedisplayedbehavioralandmotordysfunctionwhilemicecarrying65CAGrepeatsshowedamildphenotypeProgressivemuscleweaknessandatrophywasobservedinAR120miceandwasassociatedwiththelossofalphamotorneuronsinthespinalcordTherewasnoevidenceofneurodegenerationinotherbrainstructuresMotordysfunctionwasobservedinbothmaleandfemaleanimalssuggestingthatthepolyglutaminerepeatexpansionmaycauseadominantgainoffunctionmutationinARThemalemicedisplayedaprogressivereductioninspermproductionconsistentwithtestisdefectsreportedinhumanpatientsKatsunoetal(2002)foundthattheSBMAneurologicphenotypewasmarkedlypronouncedinmaletransgenicmicecarryinganARproteinwith97expandedCAGrepeatscomparedtofemalemiceThephenotypeinmaleswasdramaticallyrescuedbycastrationandthefewmanifestationsinthefemalemiceweremarkedlyworsenedwithtestosteroneadministrationTestosteroneintheuncastratedmalesandtreatedfemaleswasassociatedwithincreasedtranslocationofthemutantARintothenucleuswhichwasassociatedwithamoreseverephenotypeKatsunoetal(2002)concludedthatnuclearlocalizationofmutantARwasimportantininducingneuronalcelldysfunctionanddegenerationUsinganNterminalfragmentofthehumanARproteinChanetal(2002)studiedSBMAinDrosophilaExpressionofapathogenicARproteinwithanexpandedpolyglutaminerepeatinDrosophilaresultedinnuclearandcytoplasmicinclusionformationandcellulardegenerationpreferentiallyinneuronaltissuesFlieswithacompromisedubiquitinproteasomepathwayshowedenhanceddegenerationanddecreasedpolyglutamineproteinsolubilitywhereasoverexpressionofHsp70(see140550)modulatedneurodegenerationTheauthorssuggestedthatposttranslationalproteinmodificationincludingtheubiquitinproteasomeandtheUBL1(601912)pathwaysmaymodulatepolyglutaminepathogenesisTakeyamaetal(2002)foundthatDrosophilaeyephotoreceptorneuronswithtargetedexpressionofanexpandedARproteinshowedincreasedneurodegenerationfollowingingestionofeitherandrogenagonistsorantagonistsFurtherproteinstudiesindicatedthatligandbindingtothemutantexpandedproteininducedastructuralalterationoftheARproteinwithnucleartranslocationTostudythecellularconsequencesofchroniclowlevelexposuretoexpandedpolyglutamineproteinsCowanetal(2003)constructedmousecelllinesexpressingeitherthefulllengthARortruncatedformscontaining25or65glutaminesExpressionofthepolyglutamineexpandedtruncatedARproteinresultedintheformationofcytoplasmicandnuclearaggregatesandeventualcelldeathNuclearaggregatespreferentiallystainedpositiveforhsp72(HSPA1A140550)asensitiveindicatorofacellularstressresponseBiochemicalstudiesrevealedthatthepresenceofnuclearaggregatescorrelatedwithactivationofthecjunNterminalkinase(JNK601158)DifferentmetabolicinsultsincludingheatshocktreatmentandexposuretosodiumarseniteormenadioneprovedmoretoxictothosecellsexpressingthepolyglutamineexpandedtruncatedproteinthantocellsexpressingthenonexpandedformOnceexpressedhsp72failedtolocalizenormallyandinsteadwassequesteredwithintheproteinaggregatesTheauthorsconcludedthatabnormalstressresponsesmaycontributetoenhancedcellvulnerabilityincellsexpressingpolyglutamineexpandedproteinsandmayincreasethepropensityofsuchcellstoformcytoplasmicandnuclearinclusionsSopheretal(2004)foundthattransgenicmicewitha100CAGrepeatintheARgene(AR100)developedaphenotypethatwassimilartoSBMAPathologicexaminationshowedARpositivenuclearinclusionsinCNSmotorneuronsmuscleandliveranddiffuseARstaininginspinalcordmotorneuronsCoimmunoprecipitationstudiesshowedincreasedbindingofCbpbyARinaglutaminelengthdependentfashionsuggestingthatpolyglutaminetractsmayinterferewithtranscriptionOosthuyseetal(2001)reportedthatdeletionofaCbpregulatedelementintheVegfgene(192240)producedanSBMAlikephenotypeinmiceUsingPCRandproteinanalysisSopheretal(2004)founddecreasedexpressionoftheVegf164isoforminAR100micecomparedtocontrolsInvitrostudiesshowedthatVegf164supplementationandoverexpressionofCbpindependentlyrescuedARpolyglutamineinducedcelldeathSopheretal(2004)suggestedthatSBMAmotorneuronopathyinvolvesalteredexpressionofVEGFconsistentwitharoleforVEGFasaneurotropic/survivalfactorinmotorneurondiseaseYuetal(2006)foundthattransgenicmicewiththe113CAGrepeat(AR113Q)intheARgenedemonstratedandrogendependentneuromuscularweaknessaccompaniedbymyopathicandneuropathicmorphologicchangesinskeletalmuscleincludingatrophicangulatedfibersandinternalnucleiAR113Qmiceexhibitedandrogendependentearlydeathat2to4monthsofagesurgicalcastrationcompletelypreventedearlydeathPostmortemexaminationindicatedthatthemicediedofacuteurinarytractobstructionduetomyopathicchangesintheskeletalmuscleofthelowerurinarytractassociatedwithmyotonicdischargesGeneexpressionanalysisofthesemusclesshoweddecreasedexpressionoftheClcn1(118425)andScn4a(603967)genesHindlimbmuscleshowedsimilarmyopathicfeaturesanddecreasedexpressionofNt4(162662)andGdnf(600837)Yuetal(2006)concludedthatthereisanimportantmyopathiccontributiontothepathogenesisofKennedydiseaseOtherAnimalModelsInthe'transgenicadenocarcinomaofthemouseprostate'(TRAMP)modelexpressionofthetransgeneisinitiallyregulatedbyandrogensandrestrictedtotheprostateepithelialcellsofthedorsolateralandventrallobes(GingrichandGreenberg1996Gingrichetal1997)SpontaneousprostatetumorsthathistologicallyresemblethehumandiseasearisewithashortlatencyperiodandexhibitprogressionfromprostaticintraepithelialneoplasiatoseverehyperplasiaandadenocarcinomaBuchananetal(2001)presentedthefirstreportofaspontaneousARgenemutationintheTRAMPmouseandthecolocationofthismutationwithsomaticARgenemutationsidentifiedinhumanprostatetumorstoaminoacids668671(QPIF)attheboundaryofthehingeandligandbindingdomainsThesemutationsresultedinARvariantswith2to4foldincreasedtransactivationcapacityinresponsetodihydrotestosterone(DHT)andothernonclassicalligandscomparedwithwildtypeARMutationsinthisregionhadnoapparenteffectonreceptorlevelsligandbindingkineticsorDNAbindingTheauthorsconcludedthatexpressionoftheseorsimilarvariantscouldexplaintheemergenceofhormonerefractorydiseaseinasubsetofpatientsYehetal(2002)reportedtheuseofaCre/loxconditionalknockoutstrategytogenerateARknockoutmicePhenotypeanalysisshowedthattheARknockoutmalemicehadafemalelikeappearanceandbodyweightTheirtesteswere80%smallerandserumtestosteroneconcentrationswerelowerthanthewildtypemiceSpermatogenesiswasarrestedatpachytenespermatocytesThenumberandsizeofadipocyteswerealsodifferentbetweenthewildtypeandARknockoutmiceCancellousbonevolumesofARknockoutmalemicewerereducedcomparedwithwildtypelittermatesTheaveragenumberofpupsperlitterinhomozygousandheterozygousARknockoutfemalemicewaslowerthaninwildtypefemalemicesuggestingpotentialdefectsinfemalefertilityand/orovulationThemodelcouldbeusefulforstudyingandrogenfunctionsintheselectiveandrogentargettissuesinfemaleormalemiceSatoetal(2003)foundthemaleArknockout(KO)miceexhibitedtypicalfeaturesoftesticularfeminizationinexternalreproductiveorganswithgrowthretardationThegrowthcurveofmaleArKOmicewassimilartothatofwildtypefemalelittermatesuntilthetenthweekofagebutthereaftermutantmalesdevelopedobesityAclearincreaseinwetweightsofwhiteadiposetissuesbutnotbrownadiposetissueswasevidentin30weekoldmaleArKOmiceTherewasnosignificanteffectofArKOonserumlipidparametersorfoodintakeNoaccumulationoflipidswasfoundinadipocytesoffemalehomozygousArKOmiceSatoetal(2003)concludedthatARmayserveasanegativeregulatorofadiposedevelopmentinadultmalesIkedaetal(2005)foundthatArKOmalemicewithorwithoutangiotensinII(AngII106150)stimulationshowedasignificantreductioninhearttobodyweightratiocomparedwithwildtypemalemiceEchocardiographicanalysisdemonstratedimpairedconcentrichypertrophicresponseandleftventricularfunctioninAngIIstimulatedArKOmiceandWesternblotanalysisshowedthatArKOmicehadreducedAngIIinducedErksignaling(seeMAPK3601795)FurthermoreAngIIstimulationcausedelevatedcardiacfibrosisandenhancedexpressionoffibrosisrelatedgenesinArKOmicecomparedwithwildtypemiceIkedaetal(2005)concludedthattheandrogenARsystemparticipatesinnormalcardiacgrowthandmodulatescardiacadaptivehypertrophyandfibrosisduringhypertrophicstressHanetal(2005)foundthattransgenicmiceexpressinganArE231GmutationcorrespondingtohumanE251GshowedrapiddevelopmentofprostaticintraepithelialneoplasiathatprogressedtoinvasiveandmetastaticcancerTheE231GmutationoccursinahighlyconservedsignaturemotifoftheNterminaldomainthatinfluencesinteractionswithothercellularcoregulatorsSignificantpathologicchangeswerenotobservedintransgenicmiceoverexpressingwildtypeArortheT857AmutationcorrespondingtohumanT877A(3137000027)ThefindingsindicatedthattheE231GmutationinducesderegulatedgrowthandthatinsomecasesARmayactasanoncogeneShiinaetal(2006)observedthatfemaleArnullmiceappearednormalbutdevelopedprematureovarianfailure(see311360)withaberrantovariangeneexpressionEightweekoldAr/femaleswerefertilebuthadlowerfolliclenumbersandimpairedmammarydevelopmentandproducedonlyhalfofthenormalnumberofpupsperlitterFortyweekoldAr/femaleswereinfertileduetocompletelossoffolliclesGenomewidemicroarrayanalysisofmRNAfromAr/ovariesrevealedthatanumberofmajorregulatorsoffolliculogenesiswereundertranscriptionalcontrolbyArShiinaetal(2006)suggestedthatARfunctionisrequiredfornormalfemalereproductionparticularlyfolliculogenesis(selectedexamples)0001ANDROGENINSENSITIVITYCOMPLETE[ARPARTIALDEL]Brownetal(1988)usedcDNAprobesinthestudyofpatientsfrom6unrelatedfamilieswithcompleteandrogeninsensitivitysyndrome(300068)ofthereceptornegativetypeTheSouthernblotpatternwasnormalin5ofthe6patientsin1patientapartialdeletionoftheandrogenreceptorgeneinvolvingthesteroidbindingdomainwasdetected0002ANDROGENINSENSITIVITYCOMPLETE[ARPARTIALDEL]Pinskyetal(1989)andTrifiroetal(1989)reportedapatientwithcompleteandrogeninsensitivitysyndrome(300068)andadeletionintheARgenedifferentfromthatreportedbyBrownetal(1988)ThepatientalsohadmentalretardationwhichmayreflectacontiguousgenesyndromehowevernoevidenceofdeletionotherthanintheARgenecouldbeobtainedbyhybridizationwith11additionalsinglecopyprobesfromXq11q130003ANDROGENINSENSITIVITYCOMPLETE[ARARG773CYS]Inafamilywithcompleteandrogeninsensitivitysyndrome(300068)Trifiroetal(1989)identifiedaCGCtoTGCchangeinexon6thatalteredthesenseofcodon773fromargtocysPosition773oftheandrogenreceptorisin1of4regionsofitsandrogenbindingdomainthatarehomologoustocorrespondingregionsinthesteroidbindingdomainsof3othermembersofthesteroidreceptorsubfamilythatincludesthoseforprogesteroneglucocorticoidandmineralocorticoid0004ANDROGENINSENSITIVITYCOMPLETE[ARTRP717TER]Inacaseofcompleteandrogeninsensitivity(300068)Saietal(1990)demonstratedaguaninetoadeninetransitionatnucleotide2682changingcodon717fromtryptophantoatranslationstopsignalCodon717isinexon4thusthemutationpredictedsynthesisofatruncatedreceptorthatlackedmostofitsandrogenbindingdomainThesubstitutionabolishedarecognitionsequenceforHaeIII0005ANDROGENINSENSITIVITYCOMPLETE[ARVAL866MET]Inastudyofsibswithcompleteandrogeninsensitivity(300068)andreducedARbindingcapacityfordihydrotestosteroneLubahnetal(1989)foundthattheARsteroidbindingdomain(exonG)containedasingleguaninetoadeninemutationresultinginreplacementofvalinewithmethionineataminoacidresidue866AsexpectedthecarriermotherhadbothnormalandmutantARgenes0006ANDROGENINSENSITIVITYCOMPLETE[ARTRP794TER]In1of9patientswithandrogenresistance(300068)andabsentdihydrotestosteronebindinginculturedfibroblastsMarcellietal(1990)foundachangeoftryptophan794toastopcodon(TGGtoTGA)S(1)nucleaseprotectionassaysshowedthatnormallevelsofARmRNAwerepresentinskinfibroblastsofthispatientTransfectionofamutatedandrogenreceptorcDNAcontainingaterminationcodonatposition794intoeukaryoticcellsresultedinformationofanormalamountofreceptorproteinbuttheexpressedproteindidnotbinddihydrotestosterone0007ANDROGENINSENSITIVITYCOMPLETE[ARLYS588TER]Inapatientwithcompleteandrogenresistance(300068)Marcellietal(1990)foundathymineforadeninesubstitutionatnucleotideposition1924convertingtheAAAcodon588(lysine)intoaprematureterminationcodon(TAA)0008ANDROGENINSENSITIVITYPARTIAL[ARTYR761CYS]Grinoetal(1989)describedafamilyinwhichpartialandrogenresistance(312300)wasassociatedwithprofoundhypospadiasbutconsiderablevirilizationafterthetimeofexpectedpubertyTheandrogenreceptorexpressedinculturedskinfibroblastsfromanaffectedmemberofthispedigreewasnormalinamountandexhibitedonlymildqualitativeabnormalitiesThefunctionaldefectcouldbelargelyovercomebyhighdoseandrogentherapyTheclinicalfeatureswerethoseoftheReifensteinsyndromeMcPhauletal(1991)showedthattheARgeneinthisfamilycontained2structuralalterationsanAtoGchangeatposition2444inexon5thatconvertedtyrosine761tocysteineandashortenedglutaminehomopolymericsegmentinexon1thatencoded12ratherthantheusual20to22glutaminesMcPhauletal(1991)demonstratedthatthepresenceofthecysteineresidueatposition761causedarapiddissociationofdihydrotestosteronefromthereceptorproteinMarkedthermolabilityofthereceptorproteinwasdemonstrableonlyuponintroductionofpartialdeletionoftheglutaminehomopolymericsegmentinadditiontothecysteinesubstitutionThephenotypeinthisfamilyshowsthecharacteristicsreferredtoasReifensteinsyndromeMuronoetal(1995)foundthismutationinanindividualwithandrogensensitivitywithambiguousgenitaliatheyreferredtothemutationasTYR763CYS0009ANDROGENINSENSITIVITYCOMPLETE[ARLYS882TER]Inaffectedmembersofafamilywithcompleteandrogeninsensitivity(300068)Trifiroetal(1991)foundanadeninetothyminetransversioninexon8thatchangedthesenseofcodon882fromlysinetoanamber(UAG)translationterminationsignal(See1419000312fortheoriginofthedesignation'amber'See2197000030foranexampleoftheochre(UAA)typeoftranslationterminationsignal)0010ANDROGENINSENSITIVITYCOMPLETE[ARARG772CYS]Inapatientwiththereceptornegativeformofcompletetesticularfeminization(300068)Marcellietal(1991)foundasinglesubstitution(CGCtoTGC)atnucleotide2476Thisalterationresultedintheconversionofanargininetoacysteineataminoacid772BothadecreaseinARmRNAandimpairmentofthereceptormoleculeresulted0011ANDROGENINSENSITIVITYPARTIAL[ARALA771THR]In2unrelatedfamiliesKlockeretal(1992)demonstratedthattheReifensteinsyndromewasduetoaGtoAtransitionatnucleotide2314whichchangedthealaninecodon(GCC)immediatelyafterthefirstcysteineofthesecondzincfingermotifoftheandrogenreceptorintoathreoninecodon(ACC)The5patientsinthe2familiespresentedwithperineoscrotalhypospadiasandundescendedtestesAfterpubertytheyshowedsmalltestesnopalpableprostatemicropenisazoospermiaandgynecomastia0012ANDROGENINSENSITIVITYCOMPLETE[ARMET786VAL]In2Japanesesibswithcompleteandrogeninsensitivity(300068)andundetectableandrogenbindinginculturedpubicskinfibroblastsNakaoetal(1992)demonstratedasinglenucleotidesubstitutioninexonFresultinginamethioninetovaline(AtoG)changeatposition786withinthesteroidbindingdomainofARAlthoughreconstructionofthismutationbysitedirectedmutagenesisintohumanARcDNAfollowedbyexpressioninCOS1cellsledtoproductionofanormalamountandmolecularmassofimmunodetectableARproteinthemutantARshowedmarkedlylowaffinityofandrogenbinding0013PROSTATECANCER[ARVAL730MET]In1of26specimensofuntreatedorganconfinedstageBprostatecancerNewmarketal(1992)foundasomaticARmutationbystudyofgenomicDNAbyPCRfollowedbydenaturinggradientgelelectrophoresis(DGGE)SequencingrevealedaGtoAsubstitutioninexonEchangingvalinetomethionineatcodon730AnabundanceofthemutatedfragmentindicateditspresenceincellswithagrowthadvantageThemutationwasnotdetectableinperipheralbloodlymphocyteDNATheypostulatedthatsomaticmutationintheARgeneleadingtopersistentexpressioncouldgiverisetoandrogenindependentprostatecancerMutationoccurredinthehormonebindingdomaininaregionhighlyconservedamongallsteroidreceptorsNewmarketal(1992)pointedtoapossiblycomparablesituationwithanestrogenreceptormRNAvariantfoundinbreastcancerthatlackedpartofthehormonebindingdomainityieldedamutantreceptorthatwasconstitutivelyactiveintheabsenceofestrogenprovidingapotentialmechanismforestrogenindependentbreastcancergrowth(McGuireetal1991)OverexpressionofamplifiedgenesisoftenassociatedwiththeacquisitionofresistancetocancertherapeuticagentsinvitroVisakorpietal(1995)identifiedasimilarmolecularmechanisminvivoforendocrinetreatmentfailureinhumanprostatecancerthatinvolvedamplificationoftheandrogenreceptorgeneTheyfoundhighlevelARamplificationin7of23(30%)recurrenttumorsbutinnoneofthespecimenstakenfromthesamepatientspriortotherapyResultssuggestedthatARamplificationemergesduringandrogendeprivationtherapybyfacilitatingtumorcellgrowthinlowandrogenconcentrations0014SPINALANDBULBARMUSCULARATROPHYXLINKED[AR(CAG)nEXPANSION]Studying35unrelatedpatientsLaSpadaetal(1991)foundanincreasedsizeofapolymorphictandemCAGrepeat(polyglutaminetract)inthecodingregionoftheandrogenreceptorgeneTheseamplifiedrepeatswerefoundinnoneof75controlsandsegregatedwiththediseasein15familiesTheassociationwasnotlikelytobeduetolinkagedisequilibriumbecause11differentdiseasealleleswereobservedLundetal(2001)haplotyped123Kennedydisease(313200)familiesfromFinlandSwedenNorwayDenmarkGermanyBelgiumItalyJapanAustraliaandCanadaThehaplotypeanalysisshoweddifferentfounderhaplotypesaroundtheworldimplyingthattheCAGrepeatexpansionmutationinKennedydiseaseisnotauniqueeventNoparticularexpansionpronehaplotypecouldbedetectedAmong95KennedydiseasepatientswithdefinedagesatonsettheauthorsfoundaweaknegativecorrelationbetweentheCAGrepeatlengthandtheageofonset0015ANDROGENINSENSITIVITYCOMPLETE[ARARG773HIS]WhereasaCtoTtransitionincodon773changesargininetocysteine(3137000003)andresultsincompleteandrogeninsensitivity(300068)aGtoAtransitionchangesaminoacid773tohistidineandalsoresultsincompleteandrogeninsensitivity(Prioretal1992)Thefindingisconsistentwiththeevolutionarypreservationofthepositionhomologoustoarg773intheandrogenreceptor0016BREASTCANCERMALEWITHREIFENSTEINSYNDROME[ARARG607GLN]Woosteretal(1992)describedbrotherswhodevelopedinfiltratingductalcancersofthebreastatages75and55yearsrespectivelyBothwerebornwithpenoscrotalhypospadiasWoosteretal(1992)demonstratedaGtoAtransitioninexon3oftheandrogenreceptorresultinginthesubstitutionofglnforarg607whichislocatedwithinthesecondzincfingerArg607isconservedintheandrogenestrogenglucocorticoidandmineralocorticoidreceptorsWeidemannetal(1998)foundthesamemutationinanindividualwithpartialandrogeninsensitivityAt19yearsofagethepatienthadundervirilizationandendocrinefindingstypicalforandrogeninsensitivityInanattempttoimprovevirilizationhighdosetestosteroneenanthatetreatment(250mgonceaweekbyintramuscularinjection)wasbegunAfter35yearsofthistreatmentmarkedpromotionofvirilizationwasachievedieloweringofvoicemalepatternsecondaryhairdistributionmarkedgrowthofbeardandcoarsebodyhairincreaseinphallicsizeincreaseinbonemineraldensityanddecreaseinmammaryglandsize0017ANDROGENINSENSITIVITYCOMPLETE[ARVAL865MET]Inapatientwithcompleteandrogeninsensitivity(300068)KazemiEsfarjanietal(1993)identifiedaGtoAtransitioninexon7oftheandrogenreceptorwhichconvertedcodon865fromGTG(val)toATG(met)0018ANDROGENINSENSITIVITYPARTIAL[ARVAL865LEU]Inapatientwithpartialandrogeninsensitivity(312300)KazemiEsfarjanietal(1993)identifiedaGtoTtransversioninexon7oftheandrogenreceptorwhichconvertedcodon865fromGTG(val)toTTG(leu)Itwasremarkablethatamethioninesubstitutionofthissamecodon(3137000017)resultedincompleteandrogeninsensitivity0019ANDROGENINSENSITIVITYPARTIAL[ARARG855HIS]In2KuwaitibrothersborntononconsanguineousparentswhopresentedintheneonatalperiodwithsevereperinealhypospadiasbilateralcryptorchidismandmicropenisBatchetal(1993)foundaGtoAchangeinexonGoftheARgenewhichcausedanargtohissubstitutionataminoacid855The2boyshad46XYkaryotypesandshowednormaltestosteronebiosynthesisandmetabolismBothshowedaqualitativedefectinandrogenbinding(see312300)suggestingthattheandrogenreceptorwasdefective0020HYPOSPADIASPERINEAL[ARILE869MET]In2brothersborntononconsanguineousparentswhopresentedatbirthwithperinealhypospadias(300633)Batchetal(1993)foundanAtoCchangeinexon2oftheARgenewhichcausedaniletometchangeataminoacid869Bothbrothershada46XYkaryotypeandendocrineinvestigationswerenormalinbothBothshowedaqualitativedefectinandrogenbindingsuggestingthattheandrogenreceptorwasdefective0021ANDROGENINSENSITIVITYCOMPLETE[ARGLN60TER]In246XYsibswithcompletetesticularfeminization(300068)andadiminishedamountofqualitativelyabnormalARZoppietal(1993)foundaCAGtoTAGchangeatnucleotide340inexon1whichcausedaglntotermutationataminoacid60intheARgeneInvitromutagenesisstudiessuggestedthesynthesisofthemutantARisinitiateddownstreamoftheterminationcodonatreducedlevelsandthateachmoleculeisfunctionallyimpairedTheseresultsdefinedanovelmechanismcausingandrogenresistancethecombinationofdecreasedamountandfunctionalimpairmentofARcausedbyanabnormalitywithintheaminoterminusofthereceptorZoppietal(1993)determinedthatthemutationwasnotpresentina46XYfetalsiboftheprobandat9weeks'gestation0022ANDROGENINSENSITIVITYCOMPLETE[AR5KBDELEXE]Inafamilywithcompleteandrogeninsensitivity(300068)MacLeanetal(1993)found2differentdeletionsintheARgeneTwoaffectedsistersandtheirheterozygousmotherauntandgrandmotherhada5kbdeletionofexonEandsurroundingintronsAnaffected(XY)aunthada5kbdeletionofexonsFandGandsurroundingintronicsequences(3137000023)Bothdeletionshad1breakpointinthesame200bpregionofintron5buttheyextendedinoppositedirectionsBothdeletionswouldalterthereadingframeofthedownstreamexonsresultingintheproductionofabnormalreceptorsthatlackvitalpartsofthesteroidbindingdomainTheinabilityofthereceptortobindligandwouldthusrenderthetargettissuesunresponsivetoandrogens0023ANDROGENINSENSITIVITYCOMPLETE[AR5KBDELEXFG]See3137000022andMacLeanetal(1993)0024BREASTCANCERMALEWITHREIFENSTEINSYNDROME[ARARG608LYS]In1of13casesofmalebreastcancerLobaccaroetal(1993)foundbysinglestrandconformationpolymorphismanddirectsequencingaGtoAtransitionatnucleotide2185thatchangedarginine608intolysineinahighlyconservedregionofthesecondzincfingeroftheandrogenreceptorThepatientwasa38yearoldmanwithpartialandrogeninsensitivitysyndromeandnormalandrogenbindingcapacityinculturedgenitalskinfibroblastsTheauthorsnotedthepreviouslyreportedarg607toglnmutation(3137000016)TheyconcludedthatthegeneticabnormalitywasnotfortuitousAdecreaseinandrogenactionwithinbreastcellscouldaccountforthedevelopmentofmalebreastcancerbythelossofaprotectiveeffectofandrogensonthesecellsActivationofestrogenregulatedgenesbychangeintheDNAbindingcharacteristicsofthemutantandrogenreceptorcouldnothoweverberuledoutThepatientinthiscasehadmarkedlyambiguousgenitalia(micropenishypospadiasandbifidscrotum)associatedwithbilateralgynecomastiaThefindingscorrespondtothoseofReifensteinsyndrome0025ANDROGENINSENSITIVITYPARTIAL[ARARG839HIS]Beiteletal(1994)describedanarg839tohismutationinaffectedmembersof2familiesinwhomexternalgenitaliawerepredominantlyfemaleatbirthandsexofrearinghadbeenfemaleInathirdfamilytheexternalgenitaliaofaffectedmemberswerepredominantlymaleatbirthandsexofrearinghadbeenmalehowevertheseindividualscarriedanarg839tocysmutation(3137000026)Ingenitalskinfibroblastsbothmutantreceptorshadanormalandrogenbindingcapacitybuttheydifferedinselectedindicesofaffinityfordihydrotestosteroneor2syntheticandrogensIntransientlycotransfectedandrogentreatedCOS1cellsbothmutantreceptorstransactivatedareportergenesubnormallyThehis839mutantwaslessactivethanitspartnerprimarilybecauseitsandrogenbindingactivitywasmoreunstableduringprolongedexposuretoandrogen(see312300)0026ANDROGENINSENSITIVITYPARTIAL[ARARG839CYS]See3137000025Beiteletal(1994)0027PROSTATECANCER[ARTHR877ALA]In6of24specimensofprostatictissuederivedfromtransurethralresectionsinpatientswithmetastaticprostatecancerGaddipatietal(1994)foundathr877toalamutationinthehormonebindingdomainoftheARgeneThesamemutationhadbeenreportedpreviouslyinametastaticprostaticcancercelllinewhereitconferredontheandrogenreceptoranalteredligandbindingspecificitythatwasstimulatedbyestrogensprogestagensandantiandrogensGaddipatietal(1994)suggestedthatthecodon877mutantARwithalteredligandbindingmayprovideaselectivegrowthadvantageinthegenesisofasubsetofadvancedprostatecancerThestimulatoryeffectoftheusualtherapeuticagentsonthecodon877mutantARmaycontributetotreatmentrefractorydisease0028ANDROGENINSENSITIVITYCOMPLETE[ARLEU676PRO]InalargeManitobaHutteritekindredwithXlinkedreceptornegativecompleteandrogeninsensitivity(300068)Belshametal(1995)foundaTtoCtransitioninexon4thatresultedinreplacementofleucine676withprolineatasitethatisconservedinnumerousmembersofthesteroidreceptorgenefamilyThemutationatnucleotide2558wasfoundtoabolishreceptorbindingactivitywhenthemutantARwastransfectedintoCOS1cellsThemutationwasdetectedbyMspIdigestionofthePCRamplifiedexon4productThepropositusand3maternalauntshadthecompletesyndromeTheManitobaHutteritesareSchmiedeleutandevolvedfromarelativelysmallfounderpopulationthatconsistedofamaximumof124ancestralgenomes(Lewisetal1985)0029PROSTATECANCER[ARTHR877SER]MostmetastaticandrogenindependentprostatecancersexpresshighlevelsofandrogenreceptorgenetranscriptsTaplinetal(1995)identifiedpointmutationsintheARgeneinmetastaticcellsfrom5of10patientswithprostatecancersinthiscategoryOnemutationthr877toserwasinthesamecodonasthatfoundpreviouslyintheandrogenindependentprostatecancercellline(3137000027)In2ofthe5patientsthemutationswerenotdetectedintheprimarytumorsFunctionalstudiesof2ofthemutantandrogenreceptorsdemonstratedthattheycouldbeactivatedbyprogesteroneandestrogenFourdifferentmutationsintheARgenewereidentifiedin1tumor(3137000033)Wilson(1995)usedtheexpression'promiscuousreceptor'torefertothemutantreceptorthatalthoughlosingitsspecificityforandrogengainstheabilitytorespondtohormones(estradiolandprogesterone)thatitwouldnotordinarilyrecognizeUnderthesecircumstancesotherhormonescanplaythepartordinarilyreservedforandrogen0030PROSTATECANCER[ARHIS874TYR]Taplinetal(1995)foundaCATtoTATtransitionintheARgeneinmetastaticcellsofprostatecancerin1outof10patientsstudiedThenucleotidesubstitutionresultedinahis874totyraminoacidchange0031PROSTATECANCER[ARGLN902ARG]Taplinetal(1995)foundaCAAtoCGAtransitionintheARgeneinmetastaticcellsofprostatecancerin1outof10patientsstudiedThenucleotidesubstitutionresultedinagln902toargaminoacidchange0032PROSTATECANCER[ARALA721THR]Taplinetal(1995)foundaGCCtoACCtransitionintheARgeneinmetastaticcellsofprostatecancerin1outof10patientsstudiedThenucleotidesubstitutionledtoaala721tothraminoacidchange0033PROSTATECANCER[ARSER647ASN]InacaseofmetastaticandrogenindependentprostatecancerTaplinetal(1995)foundthat100%ofmetastaticcellscarriedanARgenewith4mutationsresultinginthefollowingaminoacidsubstitutionsser647toasngly724toaspleu880toglnandala896tothr0034ANDROGENINSENSITIVITYCOMPLETE[ARLEU707ARG]Lumbrosoetal(1996)investigatedthemolecularbasisofandrogenresistanceinafemalenewbornwithcompletetesticularfeminization(300068)Sequencingidentifiedapointmutationinexon4responsibleforaleucine(CTG)toarginine(CGG)replacementatcodon707ThismutationresidesintheaminoterminalpartoftheligandbindingdomainoftheARInvitrostudiesshowedthatthemutantARwasfunctionallydeficientasanandrogenbindingmoleculeFurtheritsbindingtoDNAwasreducedanditwasunabletoinducetranscriptionalactivationofanandrogenresponsivereportergene0035ANDROGENINSENSITIVITYCOMPLETE[ARCYS579PHE]Inacaseofcompleteandrogeninsensitivity(300068)Imasakietal(1996)identifiedaTGCtoTTCtransversionchangingcodon579oftheARgenefromcystopheThemutationoccurredinexonBencodingthefirstzincfingeroftheDNAbindingdomainoftheARgeneThepatientwasofthe'receptorpositivetype'iethebindingabilityoftheandrogenreceptorwasnormalbothquantitativelyandqualitativelyThenucleotideandaminoacidnumerationaccordingtothesequenceofLubahnetal(1988)wasusedtoindicatethepositionofthespecificaminoacidcodon0036ANDROGENINSENSITIVITYCOMPLETE[ARPHE582TYR]Inacaseofcompleteandrogeninsensitivitysyndrome(300068)Imasakietal(1996)identifiedaTTCtoTACtransversionchangingcodon582oftheARgenefromphetotyrThemutationoccurredinexonBencodingthefirstzincfingeroftheDNAbindingdomainoftheARgeneThepatientwasofthe'receptorpositivetype'iethebindingabilityoftheandrogenreceptorwasnormalbothquantitativelyandqualitativelyThenucleotideandaminoacidnumerationaccordingtothesequenceofLubahnetal(1988)wasusedtoindicatethepositionofthespecificaminoacidcodon0037HYPOSPADIASISOLATEDDISTALPENILESHAFT[ARPRO546SER]Sutherlandetal(1996)analyzedpeniletissuefrom40patientswhounderwentreconstructivesurgeryforvariousdegreesofhypospadiasandfoundaCtoTtransitioninexon2oftheandrogenreceptorgene(pro546toser)inonly1patientThetissuewasanalyzedbysinglestrandconformationpolymorphisminexons2to8followedbyDNAsequencingifapossiblemutationwasfoundInthechildwiththemutationthedistalshafthypospadias(300633)wasnotassociatedwithothergenitourinaryanomaliesNootherpatientshadanidentifiablemutationinthecodingsequencesoftheexonstestedOfthe26patientsofwhomadequateinformationwasobtainednonehadanaffectedfatherorbrother0038ANDROGENINSENSITIVITYPARTIAL[ARGLU2LYS]WithfewexceptionsmutationsinthehumanARgeneassociatedwithandrogeninsensitivityhavebeenlimitedtotheDNAandsteroidbindingdomainsChoongetal(1996)characterizedthenovelmolecularmechanismforAISresultingfromaGtoAtransitionatcodon2adjacenttothetranslationinitiationcodonintheNterminaldomainoftheARgenein3relatedindividualswithpartialandrogeninsensitivitysyndrome(312300)TheystatedthatthiswasthefirstreportofanaturallyoccurringmutationthatalteredthenucleotidecontextoftheATGinitiationcodonatthecriticalG+4residueresultinginreducedtranslationefficiencyThefamilypedigreeshowed5affectedindividualsin3generationsconnectedthroughcarrierfemalesinacharacteristicXlinkedinheritancepatternThephenotypewasthatofambiguousgenitalia0039ANDROGENINSENSITIVITYCOMPLETE[ARMET780ILE]Inacaseofcompleteandrogeninsensitivity(300068)Jakubiczkaetal(1997)identifiedamet780toile(M780I)missensemutationintheandrogenreceptor(AR)genewhichresultedfromaGtoTtransversionconvertingATGtoATTItispuzzlingthatBatchetal(1992)describedapatientwiththesameaminoacidsubstitutionbutthephenotypeofpartialandrogeninsensitivityJakubiczkaetal(1997)suggestedthatdifferencesintheCAGrepeatinexonAmayberesponsibleforthedifferencesinclinicalconsequencesoftheM780ImutationMutationsintheARgenecauseawidespectrumofandrogeninsensitivitysyndromesIndeedpatientswiththesamemissensemutationcanhavestronglydivergentphenotypessuggestingtheinfluenceofmodifyingfactorsThepolymorphicCAGrepeatinthefirstexonoftheARgenemaybesuchamodifyingfactorKnokeetal(1999)studiedtheinfluenceofthelengthoftheCAGrepeatonthetransactivationfunctionoftheM780ImutantARwhichcancauseeitherpartialorcompleteandrogeninsensitivitysyndromeThestudiesweredonebycotransfectionofHeLacellswithvariousCAGARexpressionvectorsandahighlyandrogenresponsiveluciferasereportergeneconstructIncontrasttothewildtypeARthetranscriptionalactivityoftheM780ImutantARcouldbeconsiderablyenhancedbynonphysiologicallyhighandrogenconcentrationsFurthermoreaninverserelationshipbetweenthenumberoftheCAGrepeatsinthemutantARanditsactivitywasobservedBoehmeretal(2001)referredtothismutationasMET771ILE0040ANDROGENINSENSITIVITYPARTIAL[ARARG846HIS]Boehmeretal(1997)describedanarg846tohis(R846H)mutationoftheARgenein2sibswithpartialandrogeninsensitivity(312300)ThemotherhadoneARallelewith14CAGsandtheotherARallelewith21CAGsBothaffectedbrothershadtheallelewith14CAGsSurprisinglyanunaffectedbrotheralsohadinheritedtheARallelewith14CAGsbutwithoutthemutationThissegregationpatternindicatedthatagermlinemosaicismwaspresentinthemotherSomaticmosaicismwasalsodemonstratedinthemotherthemother'sDNAhybridizedwithbothanormalprobeandtheR846HprobeTheintensityofthehybridizationsignaloftheR846HversusthenormalallelesuggestedthattheamountofthemutantR846Hallelewaslessthan10%ofthenormalalleleinperipherallymphocytesBoehmeretal(2001)reported246XYsibschildrenoffirstcousinparentswithpartialAISwhosharedtheR846HmutationbuthadverydifferentphenotypesOnesibwithgrade5AISwasraisedasagirltheothersibwithgrade3AISwasraisedasaboyInbothsibsserumlevelsofhormonesweremeasuredasexhormonebindingglobulin(SHBG182205)suppressiontestwascompletedandmutationanalysisoftheARgeneScatchardandSDSPAGEanalysisoftheARproteinwasperformedFurthermoresteroid5alphareductase2(SRD5A2607306)expressionandactivityingenitalskinfibroblastswereinvestigatedandtheSRD5A2genewassequencedThedecreaseinSHBGserumlevelsinanSHBGsuppressiontestdidnotsuggestdifferencesinandrogensensitivityasthecauseofthephenotypicvariationAlsoandrogenbindingcharacteristicsoftheARARexpressionlevelsandthephosphorylationpatternoftheARonhormonebindingwereidenticalinbothsibsHoweverSRD5A2activitywasnormalingenitalskinfibroblastsfromthephenotypicmalepatientbutundetectableingenitalskinfibroblastsfromthephenotypicfemalepatientThelackofSRD5A2activitywasduetoabsentorreducedexpressionofSRD5A2ingenitalskinfibroblastsfromthephenotypicfemalepatientExonandflankingintronsequencesoftheSRD5A2geneshowednomutationsineithersibThereforetheabsentorreducedexpressionofSRD5A2islikelytobeadditionaltotheAISTheauthorsconcludedthat(1)distinctphenotypicvariationinthisfamilywascausedbySRD5A2deficiencyadditionaltoAIS(2)this5alphareductasedeficiencywasduetoabsenceofexpressionofSRD5A2asshownbymolecularstudiesand(3)thedistinctphenotypicvariationinAIShereisexplainedbydifferencesintheavailabilityof5alphadihydrotestosteroneduringembryonicsexdifferentiation0041ANDROGENINSENSITIVITYPARTIAL[ARIVS2ASTA11]Bruggenwirthetal(1997)foundanunusualintronicmutationinafamilyinwhich2brothersandamaternalunclehadpartialandrogeninsensitivitysyndrome(312300)Allaffectedindividualswere46XYandhadafemalehabituswithnormalfemaleexternalgenitaliaandnormalbutunderdevelopedtesteswithepididymidesandvasadeferentiapresentNoMullerianremnantswerefoundInthecodingpartandtheintron/exonboundariesoftheARgenenomutationwasfoundTheandrogenreceptordisplayednormalligandbindingparametersandmigratedasa110to112kDdoubletonSDSPAGEintheabsenceofhormoneHoweverafterculturingofthepatient'sgenitalskinfibroblastsinthepresenceofhormonetheslowermigrating114kDproteinwhichreflectshormonedependentphosphorylationwashardlydetectableFurthermorereceptorproteinwasundetectableinthenuclearfractionoffibroblastsaftertreatmentwithhormonewhichisindicativeofdefectiveDNAbindingSequencingoftheARgenerevealedaTtoAtransversion11bpupstreamofexon3inintron2AnalysisofmRNArevealedthatsplicinginvolvedacrypticsplicesitelocated71/70bpupstreamofexon3resultingingenerationofmRNAwithaninsertof69nucleotidesInadditionasmallamountofatranscriptwithadeletedexon3andaverylowlevelofwildtypetranscriptweredetectedTranslationoftheextendedtranscriptresultedinanandrogenreceptorproteinwith23aminoacidresiduesinsertedbetweenthe2zincclustersdisplayingdefectiveDNAbindinganddefectivetranscriptionactivation0042ANDROGENINSENSITIVITYPARTIAL[ARLEU172TER]Inanadultpatientwitha46XYkaryotypepresentingwithsignsofpartialvirilization(see312300)(pubichairTannerstage4andclitoralenlargement)Holterhusetal(1997)identifiedaprematurestopcodoninexon1oftheARgeneATtoGtransversionincodon172oftheARgenewasdetectedthatreplacedtheoriginalTTA(leu)withaprematureTGAstopcodonNootherfamilymemberswereaffectedExaminationofthesequencinggelidentifiedawildtypealleleindicatingamosaicismInadditioneliminationoftheuniqueAftIIrecognitionsiteinducedbythemutationwasincompletethusconfirmingmosaicismNormalandrogenbindingstudiesdemonstratedexpressionofthewildtypeARinthepatient'sgenitalskinfibroblastsPrematurestopcodonsoftheARgeneareusuallyassociatedwithacompleteandrogeninsensitivitysyndromeHolterhusetal(1997)concludedthatsomaticmosaicismoftheARgeneshiftsthephenotypetoahigherdegreeofvirilizationthanexpectedfromthegenotypeofthemutantallelealone0043ANDROGENINSENSITIVITYPARTIAL[ARGLN798GLU]Wangetal(1998)screened234subjectswithdefectivespermatogenesisandidentifiedanazoospermicsubjectwithagln798toglu(Q798E)substitutionoftheARgeneproductThisgermlinemutationwasnotdetectedin110fertilecontrolswasassociatedwithfeaturesofminimalandrogeninsensitivityinthesubject(see312300)hadbeenrelatedtomoreseveregradesofAR(Bevanetal1996)andcausedasubtlebutsignificantdecreaseinreceptortransactivationfunctioninvitrothatwasconsistentwiththephenotypeDespitebeinginthemiddleoftheligandbindingdomainoftheARtheQ798EmutationdidnotcauseanyligandbindingdefectindicatingthatthishighlyconservedresiduehasatransactivationfunctionbutdoesnotdirectlyformpartoftheligandbindingpocketThetransactivationdefectofthemutantreceptorcanberectifiedinvitrowiththeandrogenicdrugfluoxymesteronebutnotwithmesteroloneornortestosterone0044ANDROGENINSENSITIVITYPARTIAL[MET807THR]Ongetal(1999)identifiedamet807tothrmutationintheARgeneina46XYinfantwithpartialandrogeninsensitivity(312300)Treatmentwithadihydrotestosteronegelappliedtopicallytotheperiscrotalregion3timesadayfor5weeksresultedinimprovedmalegenitaldevelopmentTheauthorsstatedthatinvitrofunctionalassayscanhelpidentifythesubsetofpatientswithambiguousgenitaliawhocouldrespondwelltoandrogentherapy0045ANDROGENINSENSITIVITYCOMPLETE[AR1BPINS179A]Inalargekindredwithcompleteandrogeninsensitivitysyndrome(300068)Zhuetal(1999)identifiedamutationinthepolymorphicCAGtrinucleotideregionofexon1oftheARgenewhereasingleAisinsertedatnucleotide179orequivalentlyaGCdinucleotideisdeletedatnucleotide180(3137000046)Bothmutationsresultinaframeshiftataminoacid60andaprematureterminationofthereceptordownstreamofthemutationpredictingamutantARwithonly79aminoacidsintheNterminuswhichprohibitsbindingtotheligandaswellasthecognateDNA0046ANDROGENINSENSITIVITYCOMPLETE[AR2BPDEL180GC]See3137000045andZhuetal(1999)0047PROSTATECANCERSUSCEPTIBILITY[ARARG726LEU]Eloetal(1995)describedanarg726toleu(R726L)germlinemutationoftheARgeneinaprostatecancerpatient(see176807)fromnorthernFinlandKoivistoetal(1999)foundthesamemutationinanotherFinnishprostatecancerpatientwhenscreeningforARmutationsbysinglestrandconformationpolymorphismin6patientswhosecancersappearedduringfinasteridetreatmentforbenignprostatichyperplasiaTheR726LmutationaffectedthehormonebindingregioninexonEandledtoactivationoftheandrogenreceptornotonlybydihydrotestosteroneandtestosteronebutalsobyestradiolThefactthatthismutationhadnotbeenfoundinanypublishedstudiesoftheARgenesuggestedthatitmightrepresentauniqueFinnishmutationMononenetal(2000)analyzeditsfrequencyinover1400specimensfromblooddonorsconsecutiveprostatecancerpatientswithnofamilyhistoryofprostatecancerandpatientswithapositivefamilyhistoryofprostatecancertoexplorethefrequencyofthismutationintheFinnishpopulationaswellasitsassociationwithprostatecancerItsfrequencyinblooddonorswas3in900(033%)Incontrast8(191%)weremutationsfoundintheprostatecancergroupwithoutfamilyhistoryand2(189%)weremutationsfoundinthehereditarygroupMononenetal(2000)suggestedthattheR726LsubstitutionintheARgenemayconferupto6foldincreasedriskofprostatecancerandmaycontributetocancerdevelopmentinupto2%ofFinnishprostatecancerpatients0048ANDROGENINSENSITIVITYSYNDROME[ARSER888SER]Inapatientwithpartialandrogensensitivitysyndrome(300068)Hellwinkeletal(2001)identifiedasinglepresumablysilentnucleotidevariation(AGCtoAGT)atcodon888inexon8oftheARgeneHoweverinthepatient'sgenitalskinfibroblastsatruncatedtranscriptof55kb(normal105kb)wasdetectedwhichlackedapartofexon8andmuchofthe3primeuntranslatedregionThetranslationproductincludes8missenseaminoacidsfromcodon886onwardfollowedbyaprematurestopcodonThemutantproteinwasshownbyinvitroexpressionanalysistolackanyresidualfunctionHoweverRTPCRproductsincluded2additionalsplicingvariantsof64and78kbinbothpatientandnormalcontrolgenitalskinfibroblastsThesesplicingvariantscomprisethecompletecodingregionbutashortened3primeuntranslatedregionThusadistinctalternativepremRNAprocessingeventleadingto2additionaltranscriptsoccursgenerallyingenitalskinfibroblastsInadditionthisprocesspartiallypreventsaberrantsplicinginthepatientandproducesasmallfractionofnormalfunctionalintactARproteinthatcouldexplainthepartialmasculinizationinthispatientTheauthorsconcludedthatanexonicsplicingmutationintheARgeneindicatesaphysiologicrelevanceoftheregularARmRNAvariantswithshortened3primeuntranslatedregionsandtheirfunctionaltranslationproductsinhumangenitaldevelopment0049ANDROGENINSENSITIVITYPARTIAL[ARIVS6GT+5]Sammarcoetal(2000)reportedan11yearoldXYgirlwithclinicalmanifestationsofimpairedandrogenbiologicaction(312300)includingfemalephenotypeblindendingvaginasmalldegreeofposteriorlabialfusionandabsenceofuterusfallopiantubesandovariesAtdiagnosisthepatienthadaFSH/LHratioaccordingtothepubertalstageundetectable17betaestradiolandhighlevelsoftestosterone(801ng/mL)Afterbilateralgonadectomyperformedattheageof11yearshistologicexaminationshowedsmallembryonicseminiferoustubulescontainingprevalentlySertolicellsandoccasionalspermatogoniatogetherwithabundantfibroustissueMolecularstudyofthepatientshowedaGtoTtransversioninposition+5ofthedonorsplicesiteinthejunctionbetweenexon6andintron6oftheARgeneAnalysisofRTPCRproductsfromARmRNAfromculturedgenitalskinfibroblastsofthepatientsuggestedthatsplicingwasdefectiveandintron6wasretainedinmostofthereceptormRNAmoleculesImmunoblottingshowedthatmostoftheexpressedproteinlackedpartoftheCterminalhormonebindingdomainandasmallamountofnormalreceptorwasobservedTheauthorsconcludedthatthiswasprobablyresponsibleforthereducedbindingcapacityingenitalskinfibroblastsofthepatient0050ANDROGENINSENSITIVITYSYNDROME[ARLEU712PHE]Holterhusetal(2000)reportedafamilywith4individualswithandrogeninsensitivitysyndrome(300068)3brothers(B1B3)andtheiruncledisplayingstrikinglydifferentexternalgenitaliaB1ambiguousB2severemicropenisB3slightmicropenisandunclemicropenisandpenoscrotalhypospadiasAllhadbeenassignedamalegenderHolterhusetal(2000)detectedthesameleu712tophe(CTTTTTL712F)ARmutationineachsubjectMethyltrienolonebindingonculturedgenitalskinfibroblastsofB2suggestedmoderateimpairmentoftheligandbindingdomainIntransactivationassaysthe712Fmutantshowedconsiderabledeficiencyatlowconcentrationsoftestosterone(00101nmol/L)ordihydrotestosterone(001nmol/L)Remarkablythisdeficiencycouldbefullyneutralizedbytestosteroneconcentrationsgreaterthan10nmol/LHencethe712FARcouldswitchitsfunctionfromsubnormaltonormalwithinthephysiologicconcentrationrangeoftestosteroneThiswasreflectedbyanexcellentresponsetotestosteronetherapyinB1B2andtheuncleTheauthorsconcludedthattakingintoaccountthewelldocumentedindividualandtimedependentvariationintestosteroneconcentrationinearlyfetaldevelopmenttheirobservationsillustratedthepotentialimpactofvaryingligandconcentrationsfordistinctcasesofphenotypicvariabilityinAIS0051ANDROGENINSENSITIVITYSYNDROME[ARGLY577ARG]Nguyenetal(2001)characterizedanovelmutationofthehumanandrogenreceptor(AR)gly577toarg(G577R)associatedwithpartialandrogeninsensitivitysyndrome(300068)G577isthefirstaminoacidofthePboxaregioncrucialfortheselectivityofreceptor/DNAinteractionAlthoughtheequivalentaminoacidintheglucocorticoidreceptor(GR138040)alsoglyisnotinvolvedinDNAinteractiontheresidueatthesamepositionintheestrogenreceptor(ER133430)gluinteractswiththe2centralbasepairsinthePuGGTCAmotifTheauthorsobservedthattheG577RmutationdoesnotinducebindingtoprobesthatarenotrecognizedbythewildtypeARHoweverbindingtothe4PuGNACAelementsrecognizedbythewildtypeARwasaffectedtodifferentdegreesresultinginanalteredselectivityofDNAresponseelementrecognitionInparticulartheG577RmutantdidnotinteractwithPuGGACApalindromesModelingofthecomplexbetweenmutantARandPuGNACAmotifsindicatesthatthedestabilizingeffectofthemutationisattributabletoastericclashbetweentheCbetaofargatposition1ofthePboxandthemethylgroupofthesecondthymineresidueintheTGTTCPyarmofthepalindromeTheauthorsconcludedthatandrogentargetgenesmaybedifferentiallyaffectedbytheG577RmutationTheystatedthatG577RwasthefirstnaturalmutationcharacterizedthatalterstheselectivityoftheAR/DNAinteraction0052ANDROGENINSENSITIVITYSYNDROME[ARSER865PRO]Monganetal(2002)reportedmonozygotictwinsdiagnosedwithcompleteandrogeninsensitivitysyndrome(AIS300068)whoeachpossessed2substitutionsintheARgene(CtoGatposition2930andTtoCatposition2955bothinexon7)leadingtophe856toleu(F856L3137000053)andser865topro(S865P)mutationsrespectivelyNeitherparentwasfoundtobeacarrierforthesemutationsindicatingthatthedoublemutationarosedenovoBothmutationswererecreatedbysitedirectedmutagenesisandcomparedfunctionallywiththewildtypereceptorTheF856LmutationdidnotaffectandrogenbindingwhenexpressedinCOS1cellsnordiditdecreaseandrogendependenttransactivationintransfectedHeLacellsHowevertheS865PmutationcompletelyablatedandrogenbindingandtransactivationTheauthorsconcludedthatreplacementofserinebyprolineatposition865wassufficienttocausecompleteAISinthesetwins0053ANDROGENINSENSITIVITYSYNDROME[ARPHE856LEU]See3137000052andMonganetal(2002)0054ANDROGENINSENSITIVITYSYNDROME[ARARG840CYS]Chuetal(2002)reportedanarg840tocys(R840C)substitutionintheARgeneinalargeChinesepedigreewithAIS(300068)ThemutantgenemayresultininfertilityforsomeaffectedmaleswithorwithouthypospadiasHoweveritwasalsoobservedthatthemutationdidnotaffectthefertilityoftheotherpatientsThegonadotropinlevelsfor1ofthesepatientswerewithinnormalrange0055ANDROGENINSENSITIVITYCOMPLETE[ARHIS689PRO]Rosaetal(2002)describeda46XYphenotypicallyfemalepatientwithallofthecharacteristicsofcompleteandrogensensitivity(300068)ieprimaryamenorrheanoaxillaryorpubichairfemaleexternalgenitalianouterusandundescendedtestesAnAtoCtransitioninexon4oftheARgeneledtoanovelmissensehis689topro(H689P)mutationintheligandbindingdomainoftheARproteinFunctionalstudiesdemonstratedthatthemutatedARisunabletoefficientlybinditsnaturalliganddihydrotestosteroneandtotransactivateandrogenresponseelementsTheauthorsconcludedthattheiranalysisofthestructuralconsequencesoftheH689PsubstitutionsuggeststhatthismutationislikelytoperturbtheconformationofthesecondhelixoftheARligandbindingdomainwhichcontainsresiduescriticalforandrogenbinding0056ANDROGENINSENSITIVITYPARTIAL[ARGLY743VAL]ANDROGENINSENSITIVITYCOMPLETEINCLUDEDNakaoetal(1993)foundagly743toval(G743V)substitutionintheandrogenreceptorina20yearoldmalewithpartialandrogeninsensitivitysyndrome(312300)manifestinggynecomastiahypospadiasmicrophallusabsentpubichairandpalpablemammaryglandsTheaminoacidsubstitutionarosefromaGtoTtransversioninexon5oftheARgeneLobaccaroetal(1993)foundthismutationdenovoinaFrenchchildwithcompleteandrogeninsensitivitysyndrome(300068)andnegativereceptorbindingTheynotedthattheG743Vchangeisinthehormonebindingdomain0057ANDROGENINSENSITIVITYCOMPLETE[ARGLY743GLU]Inapatientwithcompleteandrogeninsensitivitysyndrome(300068)Poujoletal(2002)foundaGtoAtransversioninexon5oftheARgenethatresultedinagly743toglu(G743E)aminoacidsubstitutionThepatientwasreferredforprimaryamenorrheanormalbreastdevelopmentandcompleteabsenceofpubicandaxillaryhairattheageof15yearsPlasmatestosteronelevelswerewithintherangefornormalmalesandthekaryotypewas46XY0058ANDROGENINSENSITIVITYCOMPLETE[ARINS/DELEX5]Vilchisetal(2003)studiedafamilyinwhich446XYindividualsin3sibshipsof2separategenerationshadcompleteandrogeninsensitivityAnovelinsertion/deletionmutationinexon5oftheARgenewasdemonstratedAdeletionof7bpwasreplacedbyaninsertionof11nucleotideswhichrepresentedaduplicationoftheadjacentdownstreamsequenceThemutationresultedinaframeshiftthatintroducedaprematureTGAterminationsignal9codonsdownstreamTherearrangementpredictedatruncationoftheandrogenreceptortherebydeletingalargeportionoftheligandbindingdomainTheysuggestedthatthisrepresentedthefirstinsertion/deletionmutationoftheARgeneandthatithadarisenbyaslippedstrandmispairingmechanism0059AND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