《遗传学英文课件：Monogenic disorder》由会员分享，可在线阅读，更多相关《遗传学英文课件：Monogenic disorder（138页珍藏版）》请在金锄头文库上搜索。
1、WhoamI？Ages:49;Nativeplace:Xianyang,ShaanxiProvince1982.9.- 1986.6. DeptofBiology,Qinghai Normal University.B.S.1986.7.- 1990.8. Middle School No. 2 of Delingha,Qinghai.1990.9.- 1993.6. DeptofMedicalGenetics,Shanghai Medical University.M.S.1993.9.- 1996.7. StateKeyLabofGeneticEngineering,Instituteof
2、Genetics, Fudan University. PhD1996.8.- 1998.6. StateKeyLabofMedicalNeurobiology,Shanghai Medical University.Postdoctor1998.7.-1999.11. StateKeyLabofGeneticEngineering,InstituteofGenetics,Fudan University.Associate Professor1999.12.2004.8. DeptofGenetics,SchoolofMedicine,Ningbo University. Associate
3、 Professor, Professor2004.9.-,DeptofCellBiologyandMedicalGenetics,SM,ZJU.ProfessorPapersinMolecular Medicine Reports, European Journal of Surgical Oncology, Thyroid,Gene,Anatomical Record,Familial Cancer,PLoS ONE,Genetic Testing and Molecular Biomarkers,Prenatal Diagnosis,European Journal of Dermato
4、logy, American Journal of Ophthalmology,American Journal of Medical Genetics,British Journal of Dermatology,Journal of Cellular and Molecular Medicine,.Major：epidermolyticpalmoplantarkeratoderma （EPPK）Major：multipleendocrineneoplasia2A(MEN-2A) NussbaumRL,etal.张咸宁张咸宁,等等.Thompson&ThompsonGeneticsinMed
5、icine,7thed.（双语版）北京大学医学出版社（双语版）北京大学医学出版社,2009. SuggestedReadingsTurnpennyP,EllardS.Emerys elements of medical genetics: With Student Consult Access. 14th edition. ChurchillLivingstone,2012JordeLB,etal.Medical genetics. 4th ed.Mosby,2010.PassargeE.Color atlas of genetics. 4th ed.ThiemeMedicalPublishe
6、rs,2013ScriverCR,etal.The metabolic and molecular bases of inherited disease.8th ed.McGraw-HillCompanies,2001RimoinDL,etal.Emery and Rimoins Principles and Practice of Medical Genetics. 5th ed.ChurchillLivingstone,2006TobiasES,etal.Essential Medical Genetics. 6th ed.Wiley-Blackwell,2011SchaafCP,etal
7、.Human Genetics: From Molecule to Medicine.LWW,2012YoungID. Medical Genetics. OUP, 2010StrachanT,ReadA.Human molecular genetics.4th ed.GarlandScience,2010TopJournalsofMolecularMedicineCNSNEJMLancetNatureMedicineNatureGeneticsAJHGAJMGNat.Rev.Genet.Annu.Rev.GenomicsHum.Genet.Annu.Rev.Genet.TrendsMolMe
8、dGenomeRes.Hum.Mol.Genet.Hum.Mutat.J.Med.Genet.GeneticsinMedicineUsefulInternetInformationonanymendelianphenotype: www.omim.orgGenomedata:www.ensembl.org;http:/genome.cse.ucsc.eduInformationonproteins:http:/ca.expasy.orgBiomedicalliterature:www.ncbi.nlm.nih.gov/entrez/Humangenemutationdatabase:www.h
9、gmd.orgHumandiseasegeneslist:http:/bioinfo.weizmann.ac.il/cardsGeneticdiagnosis:www.genetests.org 1966:MIM（McKusickVA,1921-2008）http:/www.omim.orgLastupdated:7/31/2014.Numbersofreference:88.Pubmedsearchreferences:93564 !Monogenicdisorder(Patternsofsingle-genedisorder)ZHANGXian-Ning,PhDTel：1310581927
10、1;88208367Office:C303,TeachingBuilding2014/09Genotype:Thecombinationofallelesthatanindividualpossesses.Phenotype:Thephysicalcharacteristicsofacellororganismasdefinedbyitsgeneticconstitution.Monogenicdisorder Allele:Oneofthevariantformsofageneataparticularlocus,orlocation,onacs.Differentallelesproduc
11、evariationininheritedcharacteristicssuchashaircolororbloodtype.Pedigree:Asimplifieddiagramofafamilysgenealogythatshowsfamilymembersrelationshipstoeachotherandhowaparticulartraitordiseasehasbeeninherited.Proband:Thefamilymemberwhofirstbringafamilytotheattentionofaninvestigatorisproband.Pedigree symbo
12、lsSymbolsCommonlyUsedinPedigreeChartsProband（先证者）（先证者）:III-5Pedigreedrawingsoftware：Progeny,etc.MajorPatternsofMonogenicInheritancePatternsofautosomal dominant inheritance (AD)Patternsofautosomal recessive inheritance (AR)PatternsofX-linked dominant inheritance (XD)PatternsofX-linked recessive inher
13、itance (XR)PatternsofY-linked inheritance AutosomalDominantADADADAD requiresmutationinonlyonealleletoproducedisease malesandfemalesequallyaffected familyhistoryusuallypositive,withaffectedmembersineachgeneration mayshowapparentgenerationskippingduetovariablepenetrance,variableexpressivity,orappearan
14、ceofanewmutationinthefamily Examples:Huntingtondisease,Marfansyndrome,neurofibromatosis,familialbreast/ovariancancer,myotonicdystrophyADHuntingtonDisease(HD)Aprogressivedisorderofmotor,cognitive,andpsychiatricdisturbances.Themeanageofonsetis35to44yearsandthemediansurvivaltimeis15to18yearsafteronset.
15、inheritedinanADmanner.Offspringofanindividualwithamutantallelehavea50%chanceofinheritingthedisease-causingallele. HDcase-WoodyGuthrie(1912-1967)HuntingtonDisease(HD)Frequencyestimatedtobeabout3-7/100000inpopulationsofwesternEuropeandescent.AD,HomozygotesforHDappeartohaveasimilarageofonsettoheterozyg
16、otes,butmayexhibitanacceleratedrateofdiseaseprogression.TheHDgeneistheonlygeneassociatedwithHuntingtondisease.AtrinucleotideCAG repeat expansioninExon1istheonlymutationobserved.Anticipation:TrinucleotideCAGrepeatsizesinHDNormal26Mutable27-35Reducedpenetrance36-39Fullypenetrance40Anticipationthepheno
17、menoninwhichincreasingdiseaseseverityordecreasingageofonsetisobservedinsuccessivegenerations,isknowntooccurinHD.occurs more commonly in paternal transmission of the mutated allele.ThephenomenonofanticipationarisesfrominstabilityoftheCAGrepeatduringspermatogenesis.Largeexpansions(i.e.,anincreaseinall
18、elesize27CAGrepeats)occuralmostexclusivelythroughpaternaltransmission.Mostoftenchildrenwithjuvenile-onsetdiseasehaveinheritedtheexpandedallelefromtheirfathers.4p16.3,mappedin1983.HDgene,isolatedin1993usinghaplotypeanalysisoflinkagedisequilibrium.Huntingtin,aproteinof3144aminoacidswithapredictedmolec
19、ularmassof348kd.TheCAGrepeatintheHDgeneistranslatedintoanuninterruptedstretchofglutamineresiduesthatwhenexpandedmayhavealteredstructuralandbiochemicalproperties. HuntingtonDisease(HD)Mary (35 y.o.), Samuel (30 y.o.), and Alice (29 y.o.) are siblings at 50% risk to inherit Huntington disease from the
20、ir father, John, who was found to have a mutable normal allele when he was tested following diagnosis of his brother, Bart. All three siblings chose molecular genetic testing following genetic counseling and neurologic evaluation. All have normal neurologic examinations.ClinicalCase What do these re
21、sults mean?Mary38 CAG repeatsSamuel35 CAG repeatsAlice42 CAG repeatsBartJohnMutable normalMolecular Genetic TestingDiagnosisSamuel (35 repeats) is told that he has a mutable normal allele. Expansions of 27-35 CAG repeats have never been associated with clinical symptoms of HD; however, his children
22、are at some risk to inherit an allele with a larger allele size which could result in symptomatic HD. MarySamuel (30 y.o.)35 CAG repeatsMutable normal alleleAliceMary (38 repeats) is told that she has a reduced penetrance allele. Expansions of 36-40 CAG repeats may or may not cause symptoms of HD du
23、ring a normal life span. The onset of symptoms may be later than typically observed. Marys children are at 50% risk for inheriting the abnormal allele, which could remain in the reduced penetrance range or expand into the full penetrance range. Mary (35 y.o.)38 CAG repeatsReduced penetrance alleleSa
24、muelAliceAlice (42 repeats) is told that she has a full penetrance allele. Expansions of 41 CAG repeats or greater are always associated with symptomatic HD if the individual lives a normal life span. Alices children are at 50% risk to inherit the full penetrance allele and therefore to develop HD.M
25、arySamuelAlice (29 y.o.)42 CAG repeatsFull penetrance alleleHDgene-Hero!In1983,HDwasthefirstgeneticdiseasetobelocalizedtoachromosomelocation(4p16.3)withRFLPlinkageanalysis.(Gusellaetal.)Robertson:“The beginning of the end of dilemma?” (Nature)TheHDgene,Huntingtin,wasisolatedin1993afteradecadeofinten
26、secollaborativeeffortsamongmanylaboratoriesfromvariouscountriesandofficiallydesignatedHD.(Gusellaetal.)Little:“Huntingtons disease: The end of the beginning” (Nature)LocationsofRepeatsRichards&Sutherland,TIBS,1997,22:432.Fragile X SyndromeMacrocephalyLargeearwithsoftcartilageNormallifespanCGGtrinucl
27、eotiderepeatMarfan SyndromeisaGroupofFeaturesThesefeaturesinclude:OcularLensdislocationabout70%byage6-10yearsCardiovascularAorticdilatationabout50%byage10Aorticdissectionabout50%byage48Mitralvalveprolapseabout75%byage12MusculoskeletalHeight/spanandUS/LS75%byage12yearsPectusexcavatum(“hollowchest”),7
28、5%byage15yearsDuralectasia?100%byage20yearsFamilyhistory60%-75%byage10yearsMarfanSyndrome:AnexampleofPleiotropyFrequencyestimatedtobeabout1/15000ADinheritancebutabout25%representnewmutationMutationsintheFBN1gene(15q21.1)causeMSThesemutations(200)affectProteinfoldingIntracellulartransportSecretionFor
29、mationofextracellularmicrofibrilsMS-Hyman(1954-1986),朱刚朱刚(1971-2001),武武强强(1986-2009),张佳迪张佳迪(1988-2012)OsteogenesisImperfecta(OI)-aheterogeneousgroupofgeneticdisorders(COL1A1,17q21.3-q22;COL1A2,7q22.1)-Locusheterogeneitybonefragilityreducedlifespanshortstaturedentinogenesishearinglossaffects1/10000in
30、dividualsOItypeIBluescleraeNearnormalheightFracturesHearinglossDominantinheritanceOItypeIISeverebonecompressionSoftcalvariumBluescleraePerinataldeathNewinfamilyOItypeIIIVeryshortMarkedandprogressivedeformityBlueornormalscleraeDentinogenesisimperfecta Oftennon-ambulatoryOftennewinfamilyOItypeIVNormal
31、scleraeMild-moderateshortstatureFracturesDentinogenesisimperfecta BonedeformityDominantinheritanceADnullorstructuralmutationsintypeIcollagenachaingenesleadtodifferenttypesofOIdominantnegativeeffecthaploinsufficiencygermlinemosaicismGeneticBasisofOsteogenesisImperfectaClassicEhlers-Danlossyndrome(EDS
32、)Morethan70%havemutationsinCOL5A1(9q34.2-q34.3)ofwhichathirdhaveprematureterminationcodonsRaremutationsinCOL5A2 (2q31)EvenrarerinCOL1A1 (17q21.3-q22)50%haveadenovomutationEricwas9yearsoldwhenhepresentedtoMedicalGeneticsClinicforchronicjointdislocationandchildabuse.Hispastmedicalhistorywassignificant
33、forchildabuse,forwhichhewasremovedfromhishomeonseveraloccasions.Onexaminationhehadmarkedscarringofhisforehead,chin,andknees.Hehadhemosiderindepositiononhisshinswiththinatrophicshinyskin.Hisjointswerelaxandhehadpesplanuswithweightbearingandgenurecurvatum.Hecouldstickouthistongueandtouchhisnose.Adiagn
34、osisofEhlers-DanlostypeIwasmadeandhewasreturnedtohishome,whereheonceagainsufferedabuseatthehandsofhismotherandherboyfriend.EDStypeI4.5-year-oldboyUnusualFeaturesofAutosomalDominantInheritance1.Reducedpenetrance2.Variableexpressivity3.HighfrequencyofnewmutationsAutosomalRecessive(AR)ARARARAR requires
35、mutationofbothallelestoproducedisease malesandfemalesequallyaffected higherfrequencyinconsanguineousmatings higherfrequencyofmutationcarriersinparticularethnicgroups familyhistoryoftennegative oftenassociatedwithenzymaticdefectscausingmetabolicdisorders Examples:sicklecelldisease,phenylketonuria,cys
36、ticfibrosis,spinalmuscularatrophy,WilsondiseaseARARDevelopinpersonswhoreceivetwocopiesofthemutantgene,onefromeachparentwhoisacarrier.Carrier:apersonwhohasarecessivemutatedgene,togetherwithitsnormalallele.Carriersdonotusuallydevelopdiseasebutcanpassthemutatedgeneontotheirchildren.Sicklecellanemialeth
37、aldiseaseinwhichadefect(Glu6Val)in146AA-hemoglobin,theoxygen-carryingpigmentintheblood,causesHbaggregationanddistortion(sickling)andlossofredbloodcells,producingdamagetoorgansthroughoutthebody1stidentifiedHbdisease1/600AfricanAmericansHbS -CCT GTG GAG-Pro Val Glu-HbA -CCT GAG GAG-Pro Glu Glu-6Cystic
38、Fibrosis(CF)SevereprogressivediseaseofthebronchialsystemandgastrointestinaltractDisturbedfunctionofachlorideionchannelbymutationsofonegene,CFTR(Cysticfibrosistransmembraneconductionregulator)on7q31.3,24exons,6.5-kbtranscript,1480aminoacids.ARDiseaseincidenceapprox.1:2000inCaucasian.CFTRGene1stgeneid
39、entifiedbypositional cloningIdentifiedbytheresearchgroupledbyDr.Lap-CheeTsui(徐徐立之立之)atToronto,Canada-(1989)Identificationofthecysticfibrosisgene:chromosomewalkingandjumping.Science245:1059-1065.-(1989)Identificationofthecysticfibrosisgene:cloningandcharacterizationofcomplementaryDNA.Science245:1066-
40、1073.-(1989)Identificationofthecysticfibrosisgene:geneticanalysis.Science245:1073-1080. CFOtherExamplesofARDisordersPhenylketonuria(PKU):Genelocus(PAH):12q22-24.Diseaseincidence1:16000,cirrhosisofliver,galactosuriaandmentalretardation.Mutationsinthegeneforphenylalaninehydroxylase.Albinism:Apigmentle
41、ss“white”phenotype,determinedbyamutationinagenecodingforapigment-synthesizingenzyme.Spinalmuscularatrophy(SMA)Adisordercharacterizedbydegenerationoflowermotorneuronsandoccasionallybulbarmotorneuronsleadingtoprogressivelimbandtrunkparalysisaswellasmuscularatrophy.Itisaclinicallyandgeneticallyheteroge
42、neousgroupofneuromusculardiseases.It is the second most common lethal autosomal recessive disorder after cystic fibrosis in Caucasian populationswithanoverallincidenceof1in10000livebirthsanda carrier frequency of approximately 1 in 50.Spinalmuscularatrophy(SMA)Wilsondisease:Cutoxicity,ARWilsonSAK.Br
43、ain,1912;34:295-507 Wilsondisease:Before/AfterpenicillaminetherapyX-linkedRecessive(XR)XRXRXRXR duetoarecessivemutationlocatedontheX-chromosome malespredominantlyorexclusivelyaffected mothersarecarriers nomale-to-maletransmission somecasesduetoappearanceofanewmutationinthefamily Examples:Duchennemus
44、culardystrophy(DMD),colorblindness,hemophiliaA,glucose-6-phosphatedehydrogenase(G6PD)deficiencyXRXRHemizygote:nocorrespondinglociontheYchromosome,onlyonealleleofeachXchromosomelocus.XRDuchenneMuscularDystrophy(DMD)(AlsoknownasPseudohypertrophic)DefinitionOneofninetypesofmusculardystrophy,agroupofgen
45、etic,degenerativediseasesprimarilyaffectingvoluntarymuscles.CauseAnabsenceofdystrophin,aproteinthathelpskeepmusclecellsintact.OnsetEarlychildhood-about2to6years.SymptomsGeneralizedweaknessandmusclewastingfirstaffectingthemusclesofthehips,pelvicarea,thighsandshoulders.Calvesareoftenenlarged.Progressi
46、onDMDeventuallyaffectsallvoluntarymuscles,andtheheartandbreathingmuscles.Survivalisrarebeyondtheearly30s.AlessseverevariantisBeckermusculardystrophy.InheritanceXR.DMDprimarilyaffectsboys(1/3500world-wide),whoinheritthediseasethroughtheirmothers.WomencanbecarriersofDMDbutusuallyexhibitnosymptoms.DMDD
47、MD:GowersmaneuverGeneticsofDMDoccurringinabout1in3500males,onsetinearlychildhood,deathby3rddecademalebirths;X-linkedrecessive,lethalinmales1/3ofpatientsarenewmutants;2/3havecarriermothersdystrophin,Xp21,Extremely large gene(more than 2000 kb), 79 exons.Highmutationrate,probablyduetolargesizeofgene,6
48、0%to65%ofthemutationsaredeletions,andabout6%areduplications,Allelicmutationsinthesamegenecauseamilderdisorder,Beckermusculardystrophy.DMD (OMIM310200):Xp21.2,79Exons,2.4mbOtherExamplesofXRHemophilia A:aclassicalexampleantiHemophiliafactordeficiency.Glucose-6-Phosphate dehydrogenase deficiency (G6PD)
49、:G6PDisinthehexosemonophosphatepathway,theonlyNADPH-generationprocessinmatureredcells,whichlackthecitricacidcycle.ForthisreasonG6PDdeficiencyhasadversephysiologiceffects.Deficiencyoftheredcellenzyme,invariousforms,isthebasisoffavism,primaquinesensitivityandsomeotherdrug-sensitivehemolyticanemias,ane
50、miaandjaundiceinthenewborn,andchronicnonspherocytichemolyticanemiaRed- green color blindness:Colorblindnessafflicts8%ofmalesand0.04%ofhumanfemales.X-linkeddominant(XD)XDXD duetoadominantmutationlocatedontheX-chromosome malesandfemalesusuallyequallyaffected nomale-to-maletransmission;alldaughtersofan
51、affectedfatherareaffected Examples:hypophosphatemicrickets,incontinentiapigmentiXDExamplesofXDDisordersVitamin D-resistant rickets:Therewerenoinstancesofmale-to-maletransmissionofeitherbonediseaseorhypophosphatemia,andalldaughtersofhypophosphatemicmaleswerethemselveshypophosphatemic.Affectedpersonss
52、howareductioninrenalphosphateTmtoabout50%ofnormal.Malesandfemalesarenotsignificantlydifferentinthisrespect.causedbymutationinthephosphate-regulatingendopeptidasegene(PHEX).VitaminD-resistantrickets:Xp22.2-p22.1Y-linkedHairedearsY-linkedDisorderstheyarealwayspassedfromfathertoson,andtheyneverappearin
53、femalesSRY(sex-determiningregionY):Analysisofsuchindividualshasrevealedsomeofthemoleculesinvolvedinsexdetermination,includingonecalledSRY,whichisimportantfortestisformation.Thetestis-determiningfactor(TDF),formedundertheinfluenceoftheSRYgene,inducesthedevelopmentofthefetaltestisfromanundifferentiate
54、dgonad.Factorsaffectingpedigreepatterns OnsetagePleiotropy:multipleeffectsofasinglegene(onegene,morethanoneeffect)Genetic heterogeneityExpressivityandpenetranceCoefficientofrelationshipandconsanguineousmarriageSex-limited phenotypesandsex-influenced phenotypesgenomic imprintingAnticipationXinactivat
55、ion,Pleiotropymultipleeffectsofasinglegene(onegene,morethanoneeffect)E.g.:Marfansyndrome(FBN1gene) GeneticHeterogeneityThephenomenonthatadisordercanbecausedbydifferentallelicornon-allelicmutations.LocusheterogeneityAllelicheterogeneityPhenotypic(Clinical)heterogeneityGeneticHeterogeneityAllelicheter
56、ogeneity:Inapopulation,theremaybeanumberofdifferentmutantallelesatasinglelocus.Inanindividual,thesameorsimilarphenotypesmaybecausedbydifferentmutantallelesratherthanbyidenticalallelesatthelocus. E.g.:nearly1400differentmutationshavebeenfoundworldwideintheCFTRamongpatientswithcysticfibrosis(CF).Genet
57、icHeterogeneityLocusheterogeneity:Theproductionofidenticalphenotypesbymutationsattwoormoredifferentloci.E.g.:OsteogenesisImperfecta(OI)orBrittlebonedisease:Cs7&17.GeneticHeterogeneityPhenotypic(Clinical)heterogeneity:Thetermdescribingtheoccurrenceofclinicallydifferentphenotypesfrommutationsinthesame
58、gene. E.g.:RETgenemutationcausedHirschsprungdiseaseormultipleendocrineneoplasiatype2Aand2B orboth.ExpressivityandPenetranceExpressivity:Variationintheseverityofthephenotypicfeaturesofaparticulargene.Penetrance:Theproportionofheterozygotesforadominantgenewhoexpressatrait,evenifmildly.Sex-limited phen
59、otypesandSex-influenced phenotypesSex-limitation:Whenatraitisonlymanifestinindividualsofonesex.Sex-influence:Whenagenetictraitisexpressedmorefrequentlyinonesexthananother.Genomic imprintingThephenomenonofageneorregionofachromosomeshowingdifferentexpressiondependingontheparentoforigin.AnticipationThe
60、tendencyforsomeADdiseasestomanifestatanearlierageand/ortoincreaseinseveritywitheachsucceedinggeneration.TrinucleotideCAGrepeatsizesinHuntingtondiseaseNormal26Mutable27-35Reducedpenetrance36-39Fullypenetrance4049,XXXXYXinactivation(lyonization)InactivationofgenesononeXchromosomeinsomaticcellsoffemale
61、mammals,occurringearlyinembryoniclife,ataboutthetimeofimplantation.Arandomandpermanentevent.Monozygotictwins,differenthaircolor:?Thehusbandandwife,moreandmorealike:?MechanismsofEpigeneticInheritanceEpigenetic:The term that refers to any factor that can affect gene function without change in the genotype. DNAmethylationGenomicimprinting(parent-of-originsilencing)HistoneModificationsRegulatorynon-codingRNAs ShortinterferingRNA(siRNA)MicroRNA(mirRNA)Double-strandedRNA(dsRNA)ShortheterochromaticRNA(shRNA)Transcriptsfromrepeatedsequences(Alu,LTR)RibosomalandtransferRNAsTypesofnon-proteincodingRNAs
