Dominant negative selection of heterologous genes: isolation of
may act as novel examples of dominant negative mutations. (4). Expression of such foreign proteins could potentially interfere with cellular functions in
PPARgD5 a Naturally Occurring Dominant-Negative Splice Isoform
06 Nov 2018 HPRT was used as a reference gene and data are shown as means ± SD versus cells transfected with scrambled siRNA from four independent ...
Loop Dominance
The definition of loop polarity is then extended to multi-loop first order systems. All multi-loop systems with dominant negative polarity.
A dominant negative mutation uncovers cooperative control of
08 Apr 2022 Keywords: Wolffian Duct Dominant Negative
Remedies and Sanctions in Abuse of Dominance Cases 2006
15 May 2007 important as how to define dominance or identify abusive conduct ... positive and negative effects on consumer welfare
Mechanisms of Mendelian dominance
24 Jul 2017 examples are dominant negative mutations (DNMs) in which a defective ... In 1987 Ira Herskovitz defined DNM
Remedies and Sanctions in Abuse of Dominance Cases 2006
15 May 2007 important as how to define dominance or identify abusive conduct ... positive and negative effects on consumer welfare
A dominant negative variant of RAB5B
04 Feb 2022 and displays a dominant behavior not observed by rab-5(del) consistent with a dominant negative gene product. By definition
Review article The molecular basis of genetic dominance
protein activity; (5) dominant negative definitions and concepts and then give illustrative examples of different molecular mechanisms of dominance.
High-throughput identification of dominant negative polypeptides in
08 Apr 2019 The method can uncover numerous inhibi- tory polypeptides for a protein and thereby define small inhibitory regions even pinpointing individual ...
Mécanismes et conséquences des mutations - ipubliinsermfr
15 nov 2005 · On parle d'effet dominant négatif lorsque la protéine codée par le gène muté dénommé allèle antimorphe non seulement perd sa fonction
Terminology of Molecular Biology for dominant negative - GenScript
dominant negative A mutation whose gene product adversely affects the normal wild-type gene product within the same cell This usually occurs if the product
Exploring the Molecular Etiology of Dominant-Negative Mutations
Herskowitz (1987) provided the classical definition of dominant-negative (DN) mutations as those leading to mutant polypeptides that disrupt the activity of
Dominance (génétique) - Wikipédia
Une mutation dominante négative peut apparaitre dans une cellule somatique humaine et donner un avantage de prolifération à la cellule mutante ce qui amène à
Dominant Négatif - Forum FS Generation - Futura Sciences
Une mutation conferant un phenotype dominant négatif correspond a une mutation qui provoque la perte de fonction mais cette perte de
[PDF] Transmission des maladies génétiques - Orphanet
Définition Une maladie est transmise selon le mode autosomique dominant si le gène en cause est porté par un autosome et si la présence d'un seul allèle
Negative-dominance phenomenon with genetic variants of the
Negative dominance is a classical genetic concept involving a “poison” mutant peptide that negatively interferes with the co-expressed wild-type protein thus
Dominant negative factors in health and disease - Wiley Online Library
26 mai 2009 · Indeed Muller defined antimorphs as dominant mutations that act in opposition to the normal activity of the gene product 2 Both definitions
Mechanisms of Mendelian dominance - Wiley Online Library
26 juil 2017 · examples are dominant negative mutations (DNMs) in which a defective In 1987 Ira Herskovitz defined DNM as those leading to “mutant
Qu'est-ce qu'un dominant négatif ?
On parle d'effet dominant négatif lorsque la protéine codée par le gène muté, dénommé allèle antimorphe, non seulement perd sa fonction, mais interfère aussi avec la fonction de l'allèle normal chez les hétérozygotes.15 nov. 2005Quels sont les types de dominance ?
- La dominance (complète) : un allèle dominant et un allèle récessif composent le génotype d'un individu, et seul le caractère dominant s'exprimera dans le phénotype de ce dernier. - La dominance incomplète : le génotype est composé de deux allèles dominants différents.Pourquoi un gène est dominant ?
Un allèle est récessif si son expression implique nécessairement sa présence sur les deux chromosomes homologues. Il est dit dominant, s'il s'exprime malgré sa présence sur un seul des deux allèles et masque donc la présence du deuxième, qui est donc récessif.- Il est possible de distinguer 3 grandes classes de mutations : les substitutions nucléotidiques, les insertions/délétions de quelques nucléotides et les remaniements géniques de grande taille.
JfMedGenet1994;31:89-98
Reviewarticle
Themolecularbasisofgeneticdominance
Andrew0MWilkie
Abstract
(JMedGenet1994;31:89-98)DominantmutationsaremuchrarerthanrecessiveonesAlthoughdominantdisordersoutnumberre-cessivesbyaratioofnearly4:1inMcKusick's1992compilation,'0ascertainmentinthehumanisundoubtedlybiasedinfavourofmilddominantlyinheritedphenotypes.Bycontrast,ithaslongbeenknownfromsystematicmuta-genesisofavarietyofdiploidorganismsthatthemajorityofmutationsarerecessivetowild89 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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Genotype
AAABBBDescriptiornExamples
AisdominanttoBRecessive1isetnesC,r
_1 1?0BBpherotue:irkiowrMostsncallec:o;'ar-cdiseasesMolecularclassification
Haploinsufficiency
+Genedosage +/EctopicmRNAexpressi +/Constitutiveproteinacti iDominantnegative dStructuralfunction iToxicprotein iNewproteinFigure2Relationshipbetweengeneticandmolecularmechanismsofdominance.geneticclassificationisthatformulatedbyMuller23;therelationshipbetweenwild(A)andmutant(B)allelesisindicateddiagrammatically.Thicklinesjoincateg,thatcommonlyshowequivalence;dashedlinesconnectlessfrequentgroupings.TypesofdominantmutationIIn1932,Muller23suggestedaclassificationofdominantmutationsthatisstillwidelyquoted.IHecoinedthetermsamorph,hypomorph,andhypermorphtoreflectquantitativechangestoaZpre-existingwildtypecharacter;antimorphtoonIdescribemutualantagonisticinteractionwith-jwildtype;andneomorphforanewphenotype,notfullyantagonisedbywildtype.Hispropo-Isal,madewhenthemolecularnatureofmuta-tionwasstilluncertain(andpredatingtheidentificationofDNAasthegeneticmaterialby12years),24wasremarkableforitspres-cience.Unfortunately,laterauthorshaveIsometimestendedtoassumeaonetoonerelationshipbetweenthisclassification,basedIonclassicalgenetics,andunderlyingmolecularmechanism.Whileclearparallelsexist,theseTheareinexact(fig2).Asthisreviewfocusesontypemolecularmechanismsofdominance,IhaveaormesavoidedusingMuller'stermstohighlightthe90 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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REDUCEDGENEDOSAGE,EXPRESSION,OR
cases,theabnormalheterozygousphenotype maybebecauseoftheresultingimbalancewithNewproteinAlteredsubstratespecificityMa,antitrypsinExonshufflingTrBCR/ABLOthermechanismsRecessiveantioncogene-RetinoblastomaGenomicimprinting-Beckwith-Wiedemannsyndrome91 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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INCREASEDGENEDOSAGEApplicationofKacserandBurns'principles'8predictsthatanincreaseingenedosagetothreecopiesshouldaffectthephenotypeevenlessoftenthanareductiontoonecopy.Experi-mentalanalysissupportsthis:forexample,thesurveyofaneuploidyinDrosophilapreviouslymentioned25identifiedonlyonetriplo-lethalandonetriplo-abnormallocus.Nevertheless,cytogeneticallyvisibletrisomyinhumans(whichwillusuallyencompassatleast40to50genes)isusuallyassociatedwithphenotypicabnormality,indicatingthatasignificantminorityoflocimustbesensitiveto3versus2dosage.ItmayberelevantthattheincreaseindosageatthemRNAandproteinlevelcanexceedtheexpectedfactorof1-5;considerablygreaterrisesareobservedforsomegenesonchromosome21inDown'ssyndrome.4'Althoughthedistinctivephenotypesassoci-atedwithcertaintrisomiesmaythereforebeattributableto asmallnumberofcriticalgenes,fewofthesehavebeenspecificallyidentified.AnexceptionisPMP-22,duplicationofwhichislikelytobetheprincipalcauseoftypeICharcot-Marie-Toothdisease.44ThePMP-22regionisalsohaploinsufficient,givingthedifferentphenotypeofdominantpressurepalsies45;however,thecellularmechanismsofthesecontrastingdosageeffectsarenotunderstood.Geneamplificationinsomaticcellstomuchhighercopynumbersfrequentlyoccursincer-tainneoplasias.46AparticularlyclearexampleofhowthiscausesadominantphenotypeisprovidedbytheamplificationoftheMDM2geneinsarcomas.MDM2proteinbindstoandinactivatesthetumoursuppressorgeneP53(discussedfurtherbelow),leadingtoescapefromnormalp53regulatedcellulargrowthcontrol.47
ECTOPICORTEMPORALLYALTEREDmRNAEXPRESSIONThisgroupischaracterisedbydisturbanceoftheexquisitecontrolsofmRNAexpressionthatdictatethenormalcellulardistribution,temporalrestriction,andabsolutelevelsofmRNA.Inprinciple,alteredgeneexpressioncanariseinanygeneormessagethatcontainsaregulatorydomain,andthemolecularpatho-logyofsuchmutantsiscorrespondinglydi-verse.48Afairlyspecificillustrationoflossoftem-poralregulationisprovidedbyhereditaryper-sistenceoffetalhaemoglobin(HPFH).Knowncausesincludepointmutationoftheyglobinpromoter,whichaltersbindingoftheeryth-roidtranscriptionfactorGATA-1,49certain3'deletionsencompassingthe6andPglobingenes,50andalterationsofunidentifiedtransactingfactors.Theeffectofallthesemutationsistoabrogatethenormalswitchfromexpres-sionofyto6and1globin,whichoccursaroundthetimeofbirth.TheresultingHPFHdominantlyamelioratestheeffectsof1thalas-saemiamutations.Anexampleofectopicexpressionispro-videdbythecontrabithorax(Cbx)mutationsofDrosophila,whichinvolvetheultrabithorax(Ubx)gene,normallyexpressedintheposter-iorpartoftheembryowithananteriorbound-aryinthethirdthoracicsegment(T3).InCbxmutants,whichcompriseinsertions,inver-sions,andotherchromosomalrearrange-ments,5'UbxisalsoexpressedinT2andthisresultsinthehomeotictransformationofT2intoaT3likestructure.Similarly,dominanthomeoticmutationsoftheAntennapediageneoccurbecauseofectopicexpression:inonecasestudiedindetail(Antp73b),achromosomalinversionresultsintheentireAntpcodingregionbeingplacedunderanewpromoter.52Morecommonly,thediseasephenotypemayreflectacombinationofalterationsinthetem-poralspecificity,tissuedistribution,andabso-lutelevelofmRNAexpression.Theprimaryabnormalityusuallyliesattheleveloftran-scription,butsometimesmRNAprocessingmaybeaffected.Examplesoftranscriptionalalterationsincludethefollowing.Chromoso-maltranslocationsresultingfromerrorsinrecombinasemediatedgenerearrangementinlymphoidcellsactivateexpressionoftran-scriptionfactorslikeMYC,causingBandTcellneoplasms.5'54PromotermutationsintheCaenorhabditissexdetermininggeneher-1(theonlymemberofthispathwaysubjecttotranscriptionalcontrol)increaseexpressionlevelsandresultinpartialtransformationofXXwormsintophenotypicmales.55Increased,ectopicexpressionofachimericmRNAencodinganormalproteinaccountsforthelethalyellowmutantatthemouseagoutilocus.5657ControlofexpressionatthelevelofmRNA92 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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Alet-60ras
GTP/GDPbinding
BToll ff+4Transmembrane
CKITEIaeuar*)(*)
Extracellular(Oligomerisation)
DP53TransmembraneTyrosinekinase
MutationalhotspotsOligomerisatiRecessive
'ClasslI'dominantConstitutiveactivationHaploinsufficient
Dominantnegative
Recessive
Dominantnegative
onmissensealteration,Iaframeshiftornonsensemutationleadingtotruncation.(A)let-60ras.6465Additionalmutationsdocumentedinhumantumours63aredenoted(*).(B)Toll.66(C)KIT.38Truncationsofthetyrosinekinasedomainmayhavemixedhaploinsufficientanddominantnegativeeffects.MurineWmutations3areshowninbrackets.(D)P53.67-9Clustersofmissensemutationsarerepresentedbyblackboxes.Fourspecificmissensemutationstestedinvitroforpresenceorabsenceofdominantnegativeeffects69areshownindividually.lethality)phenotypes.Theformerisattribu-tabletostabilisationofthetruncatedproteinowingtothePESTdeletion,whilethelattermayresultfromcounteractingdestabilisationofthemutantmRNA.62Aparadigmaticexampleofconstitutivepro-teinactivationisprovidedbytheRASgenes:oncogenicpointmutationspreventGTPhy-drolysis,thusmaintainingtheproteininanactivatedstate6'65(fig3A).Similarly,activat-ingmissensemutationsatthe201ArgresidueoftheGsotprotein(whichstimulatesadenylylcyclase)havebeendocumented(assomaticmosaics)infivecasesofMcCune-Albrightsyndrome.707'Differentpointmutationsintheadultskeletalmusclesodiumchannelasubu-nitgeneSCN4Acausehyperkalaemicperiodicparalysis7273andparamyotoniacongenita,74byinterferingwithnormalvoltagesensitiveinac-tivationofthesodiumcurrent.InviewofthedifferingeffectsofsingleandtripledosageofthePMP-22genedescribedabove,itisinter-estingthatthephenotypeassociatedwithaheterozygousmissensemutation(16Leu-.Pro)resemblesthatoftripledosage,thatis,Charcot-Marie-Toothdisease.75ThissuggeststhatthemissensemutationmayincreasePMP-22activity,butthishasnotyetbeenshown.Aparticularlycomplexspectrumofmuta-tionsisencounteredattheDrosophilalocusNotch,whichencodesatransmembranereceptorproteinthattransducesavarietyofcellularsignals,andincludesanextracellulardomainrichinepidermalgrowthfactor(EGF)likerepeats.Increasedintrinsicactivityisas-sociatedwithsomeofthesocalledAbruptexmutations:thesearemissense,clusteredintheEGFdomain,andarethoughttoperturbthenormalbalanceofhomo-andheterodimericproteininteractions.7677Heterozygousnull(lossoffunction)mutationsofNotchgiveadifferentphenotype,andyetothermutantsexistthathaverecessiveordominantnegativeeffects7677(seebelow).AnotherinterestingDrosophilalocusisToll.Thisencodesatrans-membraneproteinthatprovidesanunusualexampleoftwodistinctactivationmechanisms(fig3B).66"ClassI"mutantsaremissenseandactconstitutively,possiblyowingtodirectstructuralmodulationoftheprotein."ClassII"mutantsaretruncationsthatretaintheextracellularcomponent:thisactivateswildtypeTollbyanundefinedmechanism.Mu-tantsintheclassIIgroupdiffergeneticallyfromothercategoriesofactiveproteinmutantsinthattheyarenon-functionalwhenheterozy-gousto anull.66Suchtruncationmutantsmorecommonlycausedominantnegativeeffects,asdescribedbelow.
DOMINANTNEGATIVEMUTATIONSIntheheterozygousstatethesemutantsanta-gonisetheactivityoftheremainingwildtypeallele,givingaphenotypeapproachinganull;whenhomozygous,orheterozygoustoanullmutation,theyarenon-functional.Hersko-witz78drewattentiontothevalueofthesemutationsinexperimentalstudiesandpro-posedaclassification.Themajorgroupcom-93 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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ALTEREDSTRUCTURALPROTEINSAtasimplisticlevelitiseasytounderstandwhymutationsofstructuralproteinsarefre-quentlydominant:admixtureofnormalandabnormalstructuralcomponentswilldisrupttheintegrityoftheoverallstructureona"weaklinksinachain"principle.Carefulcellbiochemicalanalysisshowsamorecomplexpicture:additionalmodulatorsoftheabnormalphenotypewillincludemRNAstability,andthedegreeofabnormalityincellularprocess-ing,secretion,andextracellularincorporationintomaturefibrils,ofthenascentprotein.MutationsoftypeIcollageninosteogenesisimperfecta(OI)8485andoffibrillininMarfansyndrome"87providethebeststudiedex-amples;inOI,thereisareasonablecorrelationbetweenpredicteddisruptionofstructurecausedbypointmutationsandexonskipsandseverityofphenotype.8485Bycontrast,lossoffunctionmutationshavemildereffects(seesectiononhaploinsufficiency).27Otherstruc-turalproteinsshowingdominantmutationsincludemyosinheavychains(unc-54(d)muta-tionsinCelegans88andhypertrophiccardio-myopathyinhumans89),andkeratins5and14(Dowling-Mearaepidermolysisbullosa).9094 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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OTHERMECHANISMSOFDOMINANCEInthissectionaresummarisedbrieflyavarietyofothermoreobscure,butneverthelessinter-estingmechanismsofdominanceactingatacellularlevel.PositioneffectvariegationinDrosophilaisthevariablereductioninexpressionofagenejuxtaposedtoheterochromatinbychromo-somerearrangement.Variegatingmutationsaregenerallyrecessiveinthattheyreduceexpressiononlyfromtherearranged(cis)chro-mosome.Thebrownlocusisunusualinthatexpressionisalsoreducedfromthenormal(trans)allele.Thisdominanteffectseemstodependonsomaticpairingbetweenthehomo-logouschromosomes,butthemechanismsofthisandother'transsensing'effectsarestilluncertain.102103Thephenomenonofnucleolardominanceinwheatreflectstherelativeexpressionoftan-demribosomalDNAfromallelicloci.Expres-sionatanindividuallocuscorrelateswiththenumberofupstreamregulatorysequences.Theseappeartocompeteforbindingtolimit-ingamountsofanactivatingprotein,sothatthemorerepeatspresent,thegreaterthelikeli-hoodofactivation.'04Segregationdistortionlocisubvertthenor-malpatternof1:1gameticsegregation,leadingtomeioticdrive.Thismayoccureitheratmeiosis,whensomepropertyofthegeneralstructureorsizeofachromosomegivesitareplicationadvantageonthespindle(chromo-somaldrive),orpostmeiotically,whendirectcompetitionbetweenthegametesoccurs(genicdrive).'05Thismayallowdisadvanta-geousmutationstospreadthroughthepopula-tion,byvirtueofcloselinkagetothedrivelocus.Awellknownexampleisthetcomplexofmouse.Unlinkednon-complementationoccurswhenheterozygousmutationsoccurattwogenescodingforinteractingproteins.Whereastheheterozygousstateforeitherlocusonitsownissilent,concurrentmutationsatbothlocicausethephenotypicthresholdtobeexceeded,andthediseasebecomesmanifest.Examplesin-cludetheinteractionofaand3tubulinmuta-tionsinDrosophila'06and,morespeculatively,theenhancedseverityofdystrophinmutationsintranstoanabnormalalleleforautosomalrecessiveFukuyamacongenitalmusculardys-trophy.107Analliedphenomenon,callednegativecom-plementationormetabolicinterference,occurswhentwoallelesatthesamelocusinteracttogiveamoreseverephenotypeinthecompound95 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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DOMINANTINHERITANCE,WITHOUT
DOMINANCEATACELLULARLEVELAlthoughtheverticaltransmissionofanab-normalcharacterisusuallyassumedtoimplydominanceofthemutationatthecellularlevel,thisisnotalwaysthecase.Inhumans,twoexceptionsaresufficientlyimportanttohavebeenincludedinthetable:recessiveantionco-genesandimprintedloci.Retinoblastomaprovidestheparadigmaticexampleofaphenotypethatsegregatesinadominantpattern,yetistheresultofamuta-tion(intheRB1gene)thatisrecessiveatacellularlevel.CellscarryingaheterozygousRB1mutationareentirelynormal,buta"secondhit"somaticmutationofthenormalalleleinatleastoneretinalcell(arelativelylikelyevent)causesretinoblastoma.'09110Ana-logousputative"antioncogenes"or"tumoursuppressors"havebeenclonedinseveralotherdominantlyinheritedcancersyndromes,includingLi-Fraumenisyndrome(P53),neuro-fibromatosistypes1and2,familialadenoma-touspolyposis(APC),andVonHippel-Lin-daudisease.Atthecellularlevel,evidenceforapurelyrecessivemechanismofgeneactionis,however,lesscertainthan withRB1,andvary-ingcontributionsfromhaploinsufficientanddominantnegativeeffectsarepossible,asdis-cussedforP53andAPC.Genomicimprintingmaygiverisetoacom-plexpatternofdominantinheritance.Ifageneistranscribedonlyfromthechromosomeori-ginatingfromoneofthetwoparents,thelocusiseffectivelyhemizygous.Mutationofthealleleonthe'active'chromosomewillcom-pletelyinactivatethelocus,whereasmutationofthealleleontheotherchromosomewillhave
gomerstogivedominantnegativeeffects.Analysisoftheparticularmutationspresentmaythereforeguideprognosis.Themechanismsofdominanceincon-ditionsassociatedwithunstabletripletrepeats(forexample,fragileXsyndrome,myotonicdystrophy,andHuntington'sdisease)arenotyetclear,andprobablyheterogeneous,witheffectsowingtoalterationsinbothmRNAexpressionandproteinfunction.Althoughthe(CGG)nexpansioninthefragileXsyndromeisassociatedwithDNAmethylationandabsenceofFMR-1geneexpression,'9inmyotonicdys-trophy,DMKallelescontaining(CTG)nexpansionsmayactuallybeoverexpressed'20(althoughthisisdisputed'2'122).Otherpoten-tialvariablesarewhethertheexpandedtripletliesinthecodingornon-codingregionoftheprotein,andthesequenceoftherepeatitself.'23Completeelucidationofthemechanismsofdominanceassociatedwithtripletrepeatexpansionmaywellyieldsomesurprises.Finally,anunderstandingofthemolecularmechanismofadiseaseisaprerequisiteforattemptinggenetherapy.Nearlyalldiseasescurrentlytargetedforgenetherapyarereces-sive,'24inwhichthegoalissimplytoreplacethemissingproduct.Itshouldbeevidentthatmostcategoriesofdominantdiseaseposeaformidablechallengetogenetherapy,butalreadythe"molecularengineers"arecontem-platingstrategiestoovercometheseproblems.ExamplesincludeantisenseRNAtherapytoantagoniseselectivelytheactionofdominantnegativemutants;orconversely,theintroduc-tionofsuchmutantstocounteracttheeffects96 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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22.PAX6gene.NatureGenet1992;2:232-8.
families.Nature1991;352:539-40.ment1992;116:799-804.35HastieND.DominantnegativemutationsintheWilmstumour(WTl)genecauseDenys-Drashsyndrome-proofthatatumour-suppressorgeneplaysacrucialroleinnormalgenitourinarydevelopment.HumMolGenet1992;1:293-5.36LittleMH,WilliamsonKA,MannensM,etal.EvidencethatWTImutationsinDenys-Drashsyndromepatientsmayactinadominantnegativefashion.HumiMolGenet1993;2:259-64.37McInnesRR,BascomRA.Retinalgenetics:anullifyingeffectforrhodopsin.NatureGenet1992;1:155-7.38SpritzRA,HolmesSA,RamesarR,GreenbergJ,CurtisD,BeightonP.MutationsoftheKIT(maststemcellgrowthfactorreceptor)proto-oncogeneaccountforacontinuousrangeofphenotypesinhumanpiebaldism.AmJHumGenet1992;51:1058-65.39Younger-ShepherdS,VaessinH,BierE,JanLY,JanYN.deadpan,anessentialpan-neuralgeneencodinganHLHprotein,actsasadenominatorinDrosophilasexdetermi-nation.Cell1992;70:911-22.40IsodaK,RothS,Nusslein-VolhardC.ThefunctionaldomainsoftheDrosophilamorphogendorsal:evidencefromtheanalysisofmutants.GenesDev1992;6:619-30.41JiangJ,LevineM.Bindingaffinitiesandcooperativeinter-actionswithbHLHactivatorsdelimitthresholdre-sponsestothedorsalgradientmorphogen.Cell1993;72:741-52.42StJohnstonD,Nusslein-VolhardC.TheoriginofpatternandpolarityintheDrosophilaembryo.Cell1992;68:201-19.43HoltzmanDM,EpsteinCJ.ThemoleculargeneticsofDownsyndrome.MolGenetMed1992;2:105-20.44PatelPI,RoaBB,WelcherAA,etal.ThegenefortheperipheralmyelinproteinPMP-22isacandidateforCharcot-Marie-ToothdiseasetypelA.NatureGeniet1992;1:159-65.45ChancePF,AldersonMK,LeppigKA,etal.DNAdeletionassociatedwithhereditaryneuropathywithliabilitytopressurepalsies.Cell1993;72:143-51.46BishopJM.Molecularthemesinoncogenesis.Cell1991;64:235-48.47OlinerJD,KinzlerKW,MeltzerPS,GeorgeDL,Vogel-steinB.Amplificationofageneencodingap53-associ-atedproteininhumansarcomas.Nature1992;358:80-3.48RuvkunG,WightmanB,BurglinT,ArasuP.Dominantgain-of-functionmutationsthatleadtomisregulationoftheCelegansheterochronicgenelin-14,andtheevolu-tionaryimplicationsofdominantmutationsinpattern-formationgenes.Development1991;S1:47-54.49MartinDIK,TsaiSF,OrkinSH.Increasedy-globinexpressioninanondeletionHPFHmediatedbyanerythroid-specificDNA-bindingfactor.Nature1989;338:435-8.50FeingoldEA,ForgetBG.ThebreakpointofalargedeletioncausinghereditarypersistenceoffetalhemoglobinoccurswithinanerythroidDNAdomainremotefromthe3-globingenecluster.Blood1989;74:2178-86.51WhiteRAH,AkamME.ContrabithoraxmutationscauseinappropriateexpressionofUltrabithoraxproductsinDrosophila.Nature1985;318:567-9.52SchneuwlyS,KuroiwaA,GehringWJ.MolecularanalysisofthedominanthomeoticAntennapediaphenotype.EMBOJ1987;6:201-6.53ClearyML.Oncogenicconversionoftranscriptionfactorsbychromosomaltranslocations.Cell1991;66:619-22.54RabbittsTH.Translocations,mastergenes,anddifferencesbetweentheoriginsofacuteandchronicleukemias.Cell1991;67:641-4.55TrentC,WoodWB,HorvitzHR.Anoveldominanttransformeralleleofthesex-determininggeneher-iofCaenorhabditiselegans.Genetics1988;120:145-57.56MillerMW,DuhlDMJ,VrielingH,etal.Cloningofthemouseagoutigenepredictsasecretedproteinubiqui-touslyexpressedinmicecarryingthelethalyellowmuta-tion.GenesDev1993;7:454-67.57MichaudEJ,BultmanSJ,StubbsLJ,WoychikRP.Theembryoniclethalityofhomozygouslethalyellowmice(A!A-V)isassociatedwiththedisruptionofanovelRNA-bindingprotein.GenesDev1993;7:1203-13.58BrueningW,BardeesyN,SilvermanBL,etal.GermlineintronicandexonicmutationsintheWilms'tumourgene(WTI)affectingurogenitaldevelopment.NatureGenet1992;1:144-8.59BickmoreWA,OgheneK,LittleMH,SeawrightA,vanHeyningenV,HastieND.ModulationofDNAbindingspecificitybyalternativesplicingoftheWilmstumorwtlgenetranscript.Science1992;257:235-7.60RogersS,WellsR,RechsteinerM.Aminoacidsequencescommontorapidlydegradedproteins:thePESThypothesis.Science1986;234:364-8.61ReedSI.GI-specificcyclins:insearchofanS-phase-promotingfactor.TrendsGenet1991;7:95-9.62MangoSE,MaineEM,KimbleJ.Carboxy-terminaltrun-cationactivatesglp-lproteintospecifyvulvalfatesinCaenorhabditiselegans.Nature1991;352:811-5.63BourneHR,SandersDA,McCormickF.TheGTPasesuperfamily:conservedstructureandmolecularmechan-ism.Nature1991;349:117-27.64BeitelG,ClarkS,HorvitzHR. TheCaenorhabditiselegansrasgenelet-60actsasaswitchinthepathwayofvulvalinduction.Nature1990;348:503-9.65HanM,SternbergPW.Analysisofdominant-negative97 on October 14, 2023 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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mutationsoftheCaenorhabditiseleganslet-60rasgene.GenesDev1991;5:2188-98.66SchneiderDS,HudsonKL,LinTY,AndersonKV.Dom-inantandrecessivemutationsdefinefunctionaldomainsofToll,atransmembraneproteinrequiredfordorsal-ventralpolarityintheDrosophilaembryo.GenesDev1991;5:797-807.67VogelsteinB.Adeadlyinheritance.Nature1990;348:681-2.68VogelsteinB,KinzlerKW.p53functionanddysfunction.Cell1992;70:523-6.69MilnerJ,MedcalfEA.Cotranslationofactivatedmutantp53withwildtypedrivesthewild-typep53proteinintothemutantconformation.Cell1991;65:765-74.70WeinsteinLS,ShenkerA,GejmanPV, MerinoMJ,Fried-manE,SpiegelAM.Activatingmutationsofthestimula-toryGproteinintheMcCune-Albrightsyndrome.NEnglJ7Med1991;325:1688-95.71SchwindingerWF,FrancomanoCA,LevineMA.Identifi-cationofamutationinthegene encodingtheasubunitofthestimulatoryGproteinofadenylylcyclaseinMcCune-Albrightsyndrome.ProcNatlAcadSciUSA1992;89:5152-6.72PtacekLJ,GeorgeAL,GriggsRC,etal.Identificationofamutationinthegenecausinghyperkalemicperiodicparalysis.Cell1991;67:1021-7.73RojasCV,WangJ,SchwartzLS,HoffmanEP,PowellBR,BrownRHJr.AMet-to-ValmutationintheskeletalmuscleNa+channela-subunitinhyperkalaemicperiodicparalysis.Nature1991;354:387-9.74McClatcheyAI,VandenBerghP,Pericak-VanceMA,etal.Temperature-sensitivemutationsintheIII-IVcytoplasmicloopregionoftheskeletalmusclesodiumchannelgeneinparamyotoniacongenita.Cell1992;68:769-74.75ValentijnLJ,BaasF,WoltermanRA,etal.IdenticalpointmutationsofPMP-22inTrembler-JmouseandCharcot-Marie-ToothdiseasetypeIA.NatureGenet1992;2:288-91.76KelleyMR,KiddS,DeutschWA,YoungMW.Mutationsalteringthestructureofepidermalgrowthfactor-likecodingsequencesattheDrosophilaNotchlocus.Cell1987;51:539-48.77XuT,RebayI,FlemingRJ,ScottgaleTN,Artavanis-TsakonasS.TheNotchlocusandthegeneticcircuitryinvolvedinearlyDrosophilaneurogenesis.GenesDev1990;4:464-75.78HerskowitzI.Functionalinactivationofgenesbydominantnegativemutations.Nature1987;329:219-22.79AmayaE,MusciTJ,KirschnerMW.ExpressionofadominantnegativemutantoftheFGFreceptordisruptsmesodermformationinXenopusembryos.Cell1991;66:257-70.80LeoneG,MaybaumL,LeePWK.Thereoviruscellattachmentproteinpossessestwoindependentlyactivetrimerizationdomains:basisofdominantnegativeeffects.Cell1992;71:479-88.81BenezraR,DavisRL,LockshonD,TurnerDL,WeintraubH.TheproteinId:anegativeregulatorofhelix-loop-helixDNAbindingproteins.Cell1990;61:49-59.82DengT,KarinM.JunBdiffersfromc-JuninitsDNA-bindinganddimerizationdomains,andrepressesc-Junbyformationofinactiveheterodimers.GenesDev1993;7:479-90.83HaradaH,FujitaT,MiyamotoM,etal.Structurallysimilarbutfunctionallydistinctfactors,IRF-1andIRF-2,bindtothesameregulatoryelementsofIFNandIFN-induciblegenes.Cell1989;58:729-39.84SykesB.Bonediseasecracksgenetics.Nature1990;348:18-20.85ByersPH,WallisGA,WillingMC.Osteogenesisimper-fecta:translationofmutationtophenotype.JMedGenet1991;28:433-42.86DietzHC,CuttingGR,PyeritzRE,etal.Marfansyndromecausedbyarecurrentdenovomissensemutationinthefibrillingene.Nature1991;352:337-9.87MilewiczDMcG,PyeritzRE,CrawfordES,ByersPH.Marfansyndrome:defectivesynthesis,secretion,andextracellularmatrixformationoffibrillinbycultureddermalfibroblasts.JClinInvest1992;89:79-86.88BejsovecA,AndersonP.FunctionsofthemyosinATPandactinbindingsitesarerequiredforCelegansthickfilamentassembly.Cell1990;60:133-40.89WatkinsH,RosenzweigA,HwangDS,etal.Characteris-ticsandprognosticimplicationsofmyosinmissensemutationsinfamilialhypertrophiccardiomyopathy.NEnglJMed1992;326:1108-14.90FuchsE,CoulombePA.Ofmiceandmen:geneticskindiseasesofkeratin.Cell1992;69:899-902.91MonplaisirN,MeraultG,PoyartC,etal.HemoglobinSAntilles:avariantwithlowersolubilitythanhemoglobinSandproducingsicklecelldiseaseinheterozygotes.ProcNatlAcadSciUSA1986;83:9363-7.92DriscollM,ChalfieM.Themec-4geneisamemberofafamilyofCaenorhabditiselegansgenesthatcanmutatetoinduceneuronaldegeneration.Nature1991;349:588-93.93JohnsonR,JacksonIJ.Lightisadominantmousemutationresultinginprematurecelldeath.NatureGenet1992;1:226-9.94CitronM,OltersdorfT,HaassC,etal.Mutationofthe3-amyloidprecursorproteininfamilialAlzheimer'sdiseaseincreasesf-proteinproduction.Nature1992;360:672-4.95BensonMD,LiepnieksJ,UemichiT,WheelerG,CorreaR.Hereditaryrenalamyloidosisassociatedwithamutantfibrinogena-chain.NatureGenet1993;3:252-5.96PepysMB,HawkinsPN,BoothDR,etal.Humanlysozymegenemutationscausehereditarysystemicamyloidosis.Nature1993;362:553-7.97FershtA,WinterG.Proteinengineering.TrendsBiochemSci1992;17:292-4.98OwenMC,BrennanSO,LewisJH,CarrellRW.Mutationofantitrypsintoantithrombin.al-antitrypsinPittsburgh(358Met--Arg),afatalbleedingdisorder.NEngl_3Med1983;309:694-8.99KimCM,GoldsteinJL,BrownMS.cDNAcloningofMEV,amutantproteinthatfacilitatescellularuptakeofmevalonate,andidentificationofthepointmutationresponsibleforitsgainoffunction.JBiolChem1992;267:23113-21.100KurzrockR,GuttermanJU,TalpazM.ThemoleculargeneticsofPhiladelphiachromosome-positiveleukemias.NEnglJfMed1988;319:990-8.101BarrFG,GaliliN,HolickJ,BiegelJA,RoveraG,Ema-nuelBS.RearrangementofthePAX3pairedboxgeneinthepaediatricsolidtumouralveolarrhabdomyosarcoma.NatureGenet1993;3:113-7.102DreesenTD,HenikoffS,LoughneyK.Apairirrg-sensi-tiveelementthatmediatestrans-inactivationisassociatedwiththeDrosophilabrowngene.GenesDev1991;5:331-40.103TartofKD,HenikoffS.Trans-sensingeffectsfromDro-sophilatohumans.Cell1991;65:201-3.104FlavellRB.Variationinstructureandexpressionofribo-somalDNAlociinwheat.Genome1989;31:963-8.105LyttleTW.Cheaterssometimesprosper:distortionofmendeliansegregationbymeioticdrive.TrendsGenet1993;9:205-10.106HaysTS,DeuringR,RobertsonB,ProutM,FullerMT.Interactingproteinsidentifiedbygeneticinteractions:amissensemutationina-tubulinfailstocomplementallelesofthetestis-specific3-tubulingeneofDrosophilamelanogaster.MolCellBiol1989;9:875-884.107BeggsAH,NeumannPE,ArahataK,etal.PossibleinfluencesontheexpressionofXchromosome-linkeddystrophinabnormalitiesbyheterozygosityforautoso-malrecessiveFukuyamacongenitalmusculardystrophy.ProcNatlAcadSciUSA1992;89:623-7.108JohnsonWG.Metabolicinterferenceandthe+-hetero-zygote.Ahypotheticalformofsimpleinheritancewhichisneitherdominantnorrecessive.AmJHumGenet1980;32:374-86.109KnudsonAG.Mutationandcancer:statisticalstudyofretinoblastoma.ProcNatlAcadAciUSA1971;68:820-3.110CaveneeWK,DryjaTP,PhillipsRA,etal.Expressionofrecessiveallelesbychromosomalmechanismsinretino-blastoma.Nature1983;305:779-84.111DeChiaraTM,RobertsonEJ,EfstratiadisA.Parentalimprintingofthemouseinsulin-likegrowthfactorIIgene.Cell1991;64:849-59.112KoufosA,GrundyP,MorganK,etal.FamilialWiede-mann-BeckwithsyndromeandasecondWilmstumorlocusbothmaptol1p15.5.AmJHumGenet1989;44:711-19.113HeutinkP,vanderMeyAGL,SandkuijlLA,etal.Agenesubjecttogenomicimprintingandresponsibleforhere-ditaryparagangliomasmapstochromosome1lq23-qter.HumMolGenet1992;1:7-10.114TommerupN.Mendeliancytogenetics.Chromosomere-arrangementsassociatedwithmendeliandisorders.JMedGenet1993;30:713-27.115BourneHR.ConsiderthecoiledcoilNature1991;351:188-90.116BourneHR.Suppressionwithadifference.Nature1991;353:696-8.117MiyoshiY,AndoH,NagaseH,etal.Germ-linemutationsoftheAPCgenein53familialadenomatouspolyposispatients.ProcNatlAcadSciUSA1992;89:4452-6.118PowellSM,ZilzN,Beazer-BarclayY,etal.APCmuta-tionsoccurearlyduringcolorectaltumorigenesis.Nature1992;359:235-7.119PierettiM,ZhangF,FuYH,etal.AbsenceofexpressionoftheFMR-1geneinfragileXsyndrome.Cell1991;66:817-22.120SabouriLA,MahadevanMS,NarangM,LeeDSC,SurhLC,KornelukRG.Effectofthemyotonicdystrophy(DM)mutationonmRNAlevelsoftheDMgene.NatureGenet1993;4:233-8.121FuYH,FriedmanDL,RichardsS,etal.Decreasedexpressionofmyotonin-proteinkinasemessengerRNAandproteininadultformofmyotonicdystrophy.Science1993;260:235-8.122Hofmann-RadvanyiH,LavedanC,RabesJP,etal.Myo-tonicdystrophy:absenceofCTGenlargedtranscriptincongenitalforms,andlowexpressionofthlenormalallele.HumMolGenet1993;2:1263-6.123MandelJL.Questionsofexpansion.NatureGenet1993;4:8-9.124MillerAD.Humangenetherapycomesofage.Nature1992;357:455-60.98 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Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.31.2.89 on 1 February 1994.
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