Genomic Imprinting and Patterns of Disease Inheritance - Nature

You're not an equal product of both parents' genes. Genomic imprinting, a process whereby only one gene copy is expressed, not only exists but, combined with ... Thispagehasbeenarchivedandisnolongerupdated   GenomicImprintingandPatternsofDiseaseInheritance By: IngridLobo,Ph.D. (WriteScienceRight) © 2008 NatureEducation  Citation: Lobo, I. (2008) GenomicImprintingandPatternsofDiseaseInheritance. NatureEducation 1(1):66 You'renotanequalproductofbothparents'genes.Genomicimprinting,aprocesswherebyonlyonegenecopyisexpressed,notonlyexistsbut,combinedwithmutations,mayleadtodisease. Aa Aa Aa   Eventhoughboth parentscontributeequallytothegeneticcontentoftheiroffspring,a developmentalprocesscalledgenomicimprintingsometimes leadstotheexclusiveexpressionofspecificgenesfromonlyoneparent.This processwasfirstdescribedin1984,whentwolaboratoriesdiscoveredamark,or "imprint,"thatdifferentiatesbetweencertaingenesonthematernaland paternalchromosomesandresultsintheexpressionofonlyonecopyofthose genesintheoffspring.Thegenesinimprintedareasofanorganism'sgenomeare expresseddependingontheparentoforigin.Asaresult,theinheritanceof boththematernalandpaternalgenesisrequiredfornormaldevelopmentto proceed(McGrath&Solter,1984;Suraniet al.,1984). Tounderstandhow imprintingworks,ratherthanlookingattheentiregenome,considertheeffect ofthisprocessonsmallerchromosomalregionsandsinglegenes.Formany diploidgenes,evenifthecopyyouinheritedfromoneparentisdefective,you haveasubstituteallelefromyourotherparent.However,inthecaseofimprinting, eventhoughtherearetwocopiesofthegene,itisasifyouarehaploidfor thisgenebecauseonlyonecopyisexpressed.Inotherwords,thereisno substituteallele,whichmakesimprintedgenesmorevulnerabletothenegative effectsofmutations.Additionally,genesandmutationsthatmightnormallybe recessivecanbeexpressedifageneisimprintedandthedominantalleleis silenced(Jirtle&Weidman,2007). DiseasesRelatedtoImprinting Asyoumightexpect, itisthereforepossiblefordiseasestooccurduetodeletionsormutationsin imprintedgenes.Diseasescanalsoresultfromuniparentaldisomy,orthe inheritanceoftwocopiesofachromosomefromoneparentandnocopyfromthe otherparent,whentheinvolvedgeneisimprinted.Additionally,diseasesare possiblewhentherearemutationsingenesresponsiblefortheimprinting processandwhentheimprintisnotsetcorrectly.Someexamplesofgenetic diseasesrelatedtoerrorsintheimprintingofspecificgenesandchromosomal regionsincludePrader-Willisyndrome,Angelmansyndrome,andseveraltypesof cancer. Prader-WilliSyndromeandAngelmanSyndrome Prader-WillisyndromewasfirstdescribedbyJohnLangdonDown(whoalsoidentifiedDownsyndrome)in1887,andlaterreportedbyAndreaPrader,AlexisLabhart,andHeinrichWilliin1956.Thisdisorderoccursinapproximatelyonein20,000birthsandisassociatedwithbehavioralandcognitiveproblems,includingmentalretardation,deficienciesinsexualdevelopmentandgrowth,hyperphagia,andobesity(Praderetal.,1956;Fallsetal.,1999). In1965,Dr.HarryAngelmanwasthefirsttoreportthesymptomsofAngelmansyndrome.Thedisorderoccursinapproximatelyonein15,000births,andthesyndromeischaracterizedbydevelopmentaldeficiencies,mentalretardation,sleepdisorders,seizures,ataxia,hyperactivity,andahappydispositionwithoutburstsoflaughter(Angelman,1965;Fallsetal.,1999). Prader-WillisyndromeandAngelmansyndromewerethefirstimprintingdiseasesdiscoveredinhumans.Thesymptomsofthesetwodisordersareverydifferent,butscientistsdiscoveredthatbothconditionsarecausedbyindistinguishabledeletionsinchromosome15inthe15q11-q13region(Knolletal.,1989).Whatdistinguishesthesedisordersistheparentaloriginoftheaffectedchromosome.Specifically,Prader-Willisyndromeiscausedbythelossofagroupofpaternallyinheritedgenesonchromosome15(Butleretal.,1986;Nichollsetal.,1989a,1989b).Incontrast,Angelmansyndromeiscausedbythelossofamaternallyinheritedgeneinthesameregionofchromosome15.ResearcherJoanKnollandhercolleaguesthusconcludedthatbothPrader-WillisyndromeandAngelmansyndromewereduetodefectsinimprintedgenes,astheimprintedregionofchromosome15normallycontainsgenesthatareeitherpaternallyormaternallyexpressed(Knolletal.,1989). Inmostcases(60%-70%),Prader-WillisyndromeiscausedbydeletionsofageneticregionthatincludesthesmallnuclearribonucleoproteinpolypeptideNgene,thenecdingene,andpossiblyothergenes(Robertson,2005).Intheremaining20%-30%ofPrader-Willipatients,thedisorderoccursbecausetheaffectedindividualhastwocopiesofmaternalchromosome15andnocopyofthecorrespondingpaternalchromosome(Robertson,2005).Thisconditioniscalledmaternalunipaternaldisomy.ItisnotyetknownhowthelossofexpressionofthesepaternallyimprintedgenesmechanisticallyresultsinPrader-Willisyndrome. ThegeneticerrorsassociatedwithAngelmansyndromeare,ofcourse,somewhatdifferent.Inparticular,TatsuyaKishinoetal.(1997)showedthatAngelmansyndromeisduetothelossofexpressionofasinglematernallyexpressedgeneintheregion,calledUBE3A.TheUBE3AgeneencodesaproteincalledE3ubiquitinligase,whichisinvolvedintargetingproteinsfordegradation,anditisonlyimprintedinthebrain.ThelossofUBE3Amayresultinabnormalitiesinnormalproteindegradationduringbraindevelopment,therebycausingAngelmansyndrome(Kishinoetal.,1997).Infact,inmostcases(65%-70%),AngelmansyndromeiscausedbymaternallyderiveddeletionsoftheUBE3Agene(Robertson,2005).However,thisconditioncanalsobecausedbypaternalunipaternaldisomy(whereinembryosinheritbothcopiesofchromosome15fromtheirfather),mutationsintheUBE3Agene,andimprintingdefects,suchasthelossofmaternalDNAmethylation(Robertson,2005). Cancer Figure1: ModeloflossofimprintingofIGF2,H19andmethylationoftheH19promoterinWilms'tumor.Innormalcells,thepaternalIGF2andmaternalH19genesareexpressed(shownlarge).SeveralsitesupstreamofH19aremethylatedonthepaternalallele(filledcircles)andunmethylatedonthematernalallele(opencircles).IntumorswithLOI,thematernalchromosomereversestoapaternalepigenotype,withapaternalpatternofmethylationoftheH19promoter,IGF2turnedon,andH19turnedoff,causingincreasedcellgrowth.LOIofH19onthematernalchromosome,whenitoccurs,couldoccurindependentlyorcouldbeinfluencedbyeventsinthepaternalchromosome.©1994NaturePublishingGroupSteenman,M.etal.LossofimprintingofIGF2islinkedtoreducedexpressionandabnormalmethylationofH19inWilms'tumor.NatureGenetics7,437(1994).Allrightsreserved. FigureDetail Inadditiontothesesyndromes,imprintinghasbeenlinkedtocertaincancers.Forinstance,Wilms'tumorisatypeofembryonickidneycancerthatisassociatedwiththeIGF2/H19locusonchromosome11.H19isanoncodingRNAofunknownfunctionwithpropertiesthatcansuppressgrowth.IGF2codesforinsulin-likegrowthfactor2,agrowthfactorhighlyexpressedinmanytypesoftumors.Thesetwogenesarebothimprinted,andnormally,onlythematernalcopyofH19andthepaternalcopyofIGF2areexpressed(Steenmanetal.,1994).Incancercells,however,bothH19andIGF2typicallylosetheirimprinting(Moultonetal.,1994;Steenmanetal.,1994).ScientistshypothesizethatifthefunctionofH19istoturnoffIGF2expression,thenthelossofH19expressioncouldresultinoverexpressionofIGF2,thusleadingtotumorigenesis(Steenmanetal.,1994). Researchhashelpedsupportthisconclusion,asWilms'tumorcellshaveshownlossofimprintingofthematernalchromosomeandaswitchtothepaternalpatternofmethylation(Steenmanetal.,1994).Moreover,ThomasMoultonandcolleaguesshowedthatH19mRNAexpressionwasdecreasedatleasttwentyfoldinmostWilms'tumors,indicatingthatH19isinactivatedintumorcells(Moultonetal.,1994).ThisresultsintheoverexpressionofIGF2andreducedexpressionofH19.BecauseH19functionstoslowcellgrowthandIGF2stimulatescellgrowth,lossofimprintingattheH19/IGF2locusresultsinuncontrolledcellgrowththatcanleadtotumorformation(Figure1;Steenmanetal.,1994). Lossofimprinting(i.e.,thelossofnormalallele-specificgeneexpression)canalsoresultincancerwhenanimprinted,normallysilentallelethatprovidescellswithagrowthadvantageisactivated,resultinginuncontrolledcellgrowthanddivision.Forexample,alongwithWilms'tumor,lossofimprintingoftheIGF2geneisassociatedwithmanyothertypesofcancer,includinglung,colon,andovariantumors(Robertson,2005).Cancerscanalsoformincasesinwhichatumorsuppressorgeneisimprinted,andthesingleexpressedcopyofthetumorsuppressorismutatedorlosesitsfunction(Jirtle&Weidman,2007). ImprintingDisordersareOntheRise Inrecentyears,therehasbeenanincreaseintheincidenceofvariousimprintingdisorders,especiallyamongchildrenconceivedusingassistedreproductivetechnologies,suchasinvitrofertilization(Maheretal.,2003;Coxetal.,2002).Becauseimprintingoccursduringgametogenesis,therearegrowingconcernsthatvariouselementsofreproductiveassistanceprocedurespreventgenesfrombeingimprintedproperlyorstablytransferredduringearlyembryonicdevelopment(Clayton-Smith,2003;Jirtle&Weidman,2007).Understandingtheprocessofimprintingandidentifyingconditionsthatinterferewithnormalimprintingmaythushelpreducetheincidenceoftheseconditions. ReferencesandRecommendedReading Angelman,H."Puppetchildren":Areportofthreecases.Developmental MedicineandChildNeurology7, 681–688(1965) Butler,M.G.,etal.Clinicalandcytogeneticsurveyof39 individualswithPrader-Labhart-Willisyndrome.AmericanJournalofMedicalGenetics23,793–809(1986) Clayton-Smith,J. Genomicimprintingasacauseofdisease.British MedicalJournal327,1121–1122 (2003)doi:10.1136/bmj.327.7424.1121 Cox,G.F.,etal.Intracytoplasmicsperminjection mayincreasetheriskofimprintingdefects.AmericanJournalofHumanGenetics71,162–164(2002) Down,J.L.MentalAffectionsofChildhoodandYouth (London,Churchill,1887) Falls,J.G.,etal.Genomicimprinting:Implications forhumandisease.AmericanJournalof Pathology154,635–647(1999) Jirtle,R.L.,& Weidman,J.R.Imprintedandmoreequal.American Scientist95,143–149(2007) Kishino,T.,etal.UBE3A/E6-APmutationscauseAngelmansyndrome.NatureGenetics15,70–73 (1997)doi:10.1038/ng0197-70(linktoarticle) Knoll,J.H.,etal.AngelmanandPrader-Willisyndromes shareacommonchromosome15deletionbutdifferinparentaloriginofthe deletion.AmericanJournalofMedical Genetics32,285–290(1989) Maher,E.R.,etal.Beckwith-Wiedemannsyndromeand assistedreproductiontechnology(ART).Journal ofMedicalGenetics40,62–64 (2003) McGrath,J.,& Solter,D.Completionofmouseembryogenesisrequiresboththe maternalandpaternalgenomes.Cell37, 179–183(1984) Moulton,T.,et al.EpigeneticlesionsattheH19 locusinWilms'tumorpatients.NatureGenetics7,440–447(1994)(linktoarticle) Nicholls,R.D.,etal.Geneticimprintingsuggestedbymaternalheterodisomyin nondeletionPrader-Willisyndrome.Nature 342,281–285(1989a)(linktoarticle) ———.Restrictionfragmentlength polymorphismswithinproximal15qandtheiruseinmolecularcytogeneticsand thePrader-Willisyndrome.AmericanJournal ofMedicalGenetics33,66–77 (1989b) Prader,A.,etal.EinSyndromvon Adipositas,Kleinwuchs,KryptorchismusundOligophrenienachMyatonieartigem ZustandimNeugeborenenalter.SchweizerischeMedizinischeWochenschrift86, 1260–1261(1956) Robertson,K.D.DNAmethylationandhumandisease.NatureReviewsGenetics 6, 597–610(2005)doi:10.1038/nrg1655(linktoarticle) Steenman,M.J.,et al.LossofimprintingofIGF2islinkedtoreducedexpressionand abnormalmethylationofH19inWilms' tumor.NatureGenetics7,433–439(1994)(linktoarticle) Surani,M.A.H.,etal.Developmentofreconstitutedmouseeggssuggestsimprintingofthe genomeduringgametogenesis.Nature308,548–550(1984)doi:10.1038/308548a0(linktoarticle) Outline | Keywords | AddContenttoGroup ArticleHistory Close Share | Cancel Revoke | Cancel Keywords KeywordsforthisArticle AddkeywordstoyourContent Save | Cancel FlagInappropriate TheContentis: Objectionable Explicit Offensive Inaccurate Comments FlagContent | Cancel Close share Close Digg MySpace Google+ StumbleUpon EmailyourFriend YourFirstName * YourLastName * YourEmailAddress * YourFriend'sEmailaddress * YourMessage* Submit | Cancel * Required Close Thiscontentiscurrentlyunderconstruction. 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