單基因遺傳病高級遺傳

Etiologyofdiseases.Foranyconditiontheoverallbalanceofgeneticandenvironmentaldeterminantscanberepresentedbyapointsomewherewithinthetriangle.ClassificationofGeneticDisordersSinglegenedisordersarecausedbydefectsinoneparticulargene,andoftenhavesimpleandpredictableinheritancepatterns.Theyaffectabout1percentofthepopulationasawhole.Epigeneticmodifications？Otherreasons?當前第1頁\共有95頁\編于星期六\2點Multifactorial(common)

Variantsingenescausingalterationoffunction“Environmental”influencesactonageneticpredispositiontoproducealiabilitytoadisease.

Oneormoreorgansystemaffected.Personaffectedifliabilityaboveathreshold.

Singlegene

(1%liveborn)Mutationsinsinglegenes(oftencausinglossoffunction)

Dominant/recessivepedigreepatterns(Mendelianinheritance).Canaffectstructuralproteins,enzymes,receptors,transcriptionfactors.

Chromosomal(0.6%liveborn)

Thousandsofgenesmaybeinvolved.Multipleorgansystemsaffectedatmultiplestagesingestation.Usuallydenovo(trisomies,deletions,duplications)butcanbe inherited(translocations).Classificationofgeneticdisorders+environmentMaleMitochondrial

Somaticmutations(cancer)當前第2頁\共有95頁\編于星期六\2點Singlegenedisorders:disordersinwhichinheritanceisduetoasinglemutantgeneMendelianinheritanceGenesareunitsofheredity,basedinDNAPhenotype(physicalorfunctionalabnormalities)Genotype(DNAchange)4.AutosomalvsX-linked

determinedbywhethertheresponsiblegeneiscarriedononeoftheautosomalchromosomesorontheXchromosome5.DominantvsRecessive,basedonphenotypicexpression當前第3頁\共有95頁\編于星期六\2點RecessiveHomozygoteswithtwocopiesofthealteredgeneareaffectedDominantHeterozygoteswithonecopyofthealteredgeneareaffectedX-linkedrecessiveMaleswithonecopyofthealteredgeneontheX-chromosomeareaffectedMale當前第4頁\共有95頁\編于星期六\2點Singlegenedisorders -Highriskstorelatives

-Dominant/recessivepedigreepatterns

-Someisolatedcasesduetonewdominantmutations

-Structuralproteins,enzymes,receptors,transcriptionfactorsI:1I:2II:1II:2II:3II:5II:6II:8III:1III:2IV:11212341ⅠⅡⅢ當前第5頁\共有95頁\編于星期六\2點當前第6頁\共有95頁\編于星期六\2點Characteristicsofsinglegeneinheritance

AutosomalDominantvertical(successive),riskofaffectedoffspring50%(bothsex)AutosomalRecessive

horizontal,multiplesibsaffected,usuallyonegeneration,consanguinity(+)riskofaffectedoffspring25%,carrier50%X-linkedDominantdaughtersofaffectedmales(+),sonsofaffectedmales(-),affectedfemalestransmitthedisordertooffspringofbothsexes,riskofaffectedoffspring50%,buttwiceasmanyaffectedfemalesasaffectedmales(nomaletomale)X-linkedRecessivemalesthroughcarrierwomen,malesaffectedalmostexclusively,femalesaffectedonlywhenaffectedfatherandcarriermotherorwithskewedX-inactivationY-linkedmalesaffected當前第7頁\共有95頁\編于星期六\2點

CharacteristicsofAutosomalDominantinheritance

1.Thephenotypeusuallyappearsineverygeneration,eachaffectedpersonhavinganaffectedparentExceptions:(1)freshmutation(2)thedisorderisnotexpressedorisexpressedonlysubtlyinapersonwhohasinheritedtheresponsiblegene.2.Anychildofanaffectedparenthasa50percentriskofinheritingthetrait3.bothmalesandfemalesareaffectedina1:1ratio

當前第8頁\共有95頁\編于星期六\2點

Autosomaldominanceinheritance

(AD)Pedigreeshowingtypicalinheritanceofaformofprogressivesensorineuraldeafness(DFNA1)inheritedasanautosomaldominanttrait當前第9頁\共有95頁\編于星期六\2點

CharacteristicsofAutosomalRecessiveInheritance

1.AnautosomalRecessivephenotype,typicallyisseenonlyinthesibshipoftheproband,notinparents,offspring,orotherrelatives.

2.bothsexesareaffectedwithequalfrequencyataratioof1:1

3.Parentsofanaffectedchildareasymptomaticcarriersofmutantalleles.heterozygousparentshaveariskof25%ofaffectedoffspring4.Theparentsoftheaffectedpersonmayinsomecasesbeconsanguineous.Thisisespeciallylikelyifthemutantgeneisrareinthepopulation.

當前第10頁\共有95頁\編于星期六\2點

AutosomalRecessiveInheritance

(AR)

當前第11頁\共有95頁\編于星期六\2點

CharacteristicsofX-linkedDominantInheritance

1.Theincidenceofthetraitismuchhigherinfemalesthaninmales(abouttwice),butaffectedfemalestypicallyhavemilder(variable)expressionofthephenotype.2.AffectedmaleswithnormalmateshavenormalsonsandAffecteddaughters.

3.BothmaleandfemaleoffspringofAffectedfemalehavea50percentriskofinheritingthephenotype.

4.Thepedigreepatternisthesameasautosomaldominantinheritance.

當前第12頁\共有95頁\編于星期六\2點

X-linkedDominantInheritance

(XD)當前第13頁\共有95頁\編于星期六\2點

CharacteristicsofX-LinkedRecessiveInheritanceTheincidenceofthetraitismuchhigherinmalesthaninfemales.Thegeneisordinarilynevertransmitteddirectlyfromfathertoson(male-to-male),butitistransmittedbyanaffectedmaletoallhisdaughters.AcarrierFemaleforanX-chromosomalmutationhasariskof50%Foranaffectedson.

Thegenemaybetransmittedthroughaseriesofcarrierfemales;affectedmalesinheritthemutantallelefromthemotheronlyHeterozygousfemalesareusuallyunaffected,butsomemayexpresstheconditionwithvariableseverityasdeterminedbythepatternofXinactivation當前第14頁\共有95頁\編于星期六\2點

X-linked

RecessiveInheritance

(XR)當前第15頁\共有95頁\編于星期六\2點Y-linkedinheritance

Gene:YA（mutantallele

）

YaGenotype:XYA

XYaholandricinheritance(全男性遺傳)male-to-male當前第16頁\共有95頁\編于星期六\2點

Y-linkedinheritance

當前第17頁\共有95頁\編于星期六\2點SinglegenedisordersHuntingtonDiseaseMyotonicDystrophyHereditaryMotorSensoryNeuropathy(HMSN)NeurofibromatosisMarfansyndromeCysticFibrosisSpinalMuscularAtrophy(SMA)DuchenneMuscularDystrophyHemophilia當前第18頁\共有95頁\編于星期六\2點Somaticmosaicismandsinglegenedisorders當前第19頁\共有95頁\編于星期六\2點Mosaicism:referstoamixtureofcellsofdifferentgeneticcompositioninoneindividual.Whenthegenotypeofonezygoteisalteredbychromosomalmis-segregationorDNAmutationinadetectablenumberofcells,itisusuallycalled‘‘mosaicism’’.Dependingonthedisorderandtheclassofmutation,ingenesforwhichtherearesufficientnumbersofpatientsstudied,6–20%ofcasesareduetosomaticmutation.Theclassesofmutation:basepairchanges,insertions/deletion(indels),shorttandemrepeatmutations,copynumbervariants(CNVs),transposon-mediatedmutations.當前第20頁\共有95頁\編于星期六\2點ExamplesofconfirmedsomaticmosaicismNeurofibromatosis1and2McCune-AlbrightsyndromeParoxysmalnocturnalhemoglobinuria(PNH)andotherdisordersdetectableinseparatedbloodcellsIncontinentiapigmentiinmalesandotherdermalandretinalexamplesofsomaticmosaicismSomaticmosaicismintheheartandkidneyMutationsinGJA5inthecardiacDNAofpatientswithatrialfibrillationAlportssyndromeinkidneySomaticmosaicismoftheneuromuscularsystemX-linkedPeriventricularheterotopiaSubcorticalbandheterotopiaSomaticmosaicismindysmorphicsyndromesTownes-BrockssyndromeCamptomelicDysplasia當前第21頁\共有95頁\編于星期六\2點Combinedgerm-lineandsomaticmosaicismMutationResearch705(2010)96–106當前第22頁\共有95頁\編于星期六\2點PaternalAgeEffect(PAE)andsinglegenedisordersTherearecertaindenovogermlinemutationsassociatedwithgeneticdisorderswhosemutationratespergenerationareordersofmagnitudehigherthanthegenomeaverage.Moreover,thesemutationsoccurexclusivelyinthemalegermlineandoldermenhaveahigherprobabilityofhavinganaffectedchildthanyoungerones.TheclassicexampleofageneticdisorderexhibitingaPAEisachondroplasia,causedpredominantlybyasingle-nucleotidesubstitution(c.1138G>A)inFGFR3.

Possibleexplanation:Mutantspermatogonialstemcellshaveaproliferativeadvantageoverunmutatedcells.HumanMolecularGenetics,2013,Vol.22,No.204117–4126當前第23頁\共有95頁\編于星期六\2點當前第24頁\共有95頁\編于星期六\2點當前第25頁\共有95頁\編于星期六\2點如何確定所研究的疾病是單基因病？確認方法主要有以下兩種：1)參考OMIM(OnlineMendelianInheritanceinMan)數據庫，根據疾病的表型或者臨床癥狀等確定是否屬于OMIM收錄的單基因病。OMIM除了簡略描述各種疾病的臨床特征、診斷、鑒別診斷、治療與預防外，還提供已知相關致病基因的連鎖關系、染色體定位、組成結構和功能、動物模型等資料，并附有經縝密篩選的相關參考文獻。網址為：2)繪制疾病的遺傳系譜圖，通過系譜圖分析其遺傳方式來判斷是否屬于孟德爾遺傳病。系譜分析法是研究人類遺傳規(guī)律的重要方法。在臨床上，常用系譜分析法來判斷某種疾病的遺傳方式。系譜圖就是從先證者（proband）（家系中第一個被醫(yī)生確診的某遺傳病的患者，或者具有某種性狀的成員）入手，追溯調查其所有家庭成員的數目、親屬關系、某種遺傳?。ɑ蛐誀睿┑姆植嫉荣Y料，按照一定格式繪制而成的圖解。當前第26頁\共有95頁\編于星期六\2點單基因病研究舉例及進展當前第27頁\共有95頁\編于星期六\2點Rieger綜合征(#MIM180500)致病基因PITX2的研究

Rieger綜合征是Axenfeld-Rieger癥候群中最為嚴重的一型典型臨床表現：眼前節(jié)發(fā)育不良，繼發(fā)青光眼口頜發(fā)育異常：先天多數牙缺失，過小牙，畸形牙面中部發(fā)育不足，下頜前突等臍殘斷回縮異常遺傳方式：常染色體顯性遺傳，發(fā)生率約為1:200,000當前第28頁\共有95頁\編于星期六\2點臨床資料：家系I先證者當前第29頁\共有95頁\編于星期六\2點Rieger綜合征相關基因和染色體區(qū)域PITX2

4q25FOXC16p25PAX611p1313q14AlltheseRieger-syndrome-associatedgenes——encodetranscriptionfactorsandhavebeenshowntoplayimportantrolesinembryonicdevelopment當前第30頁\共有95頁\編于星期六\2點測序結果Wildtype1-III:4cloned1-III:4uncloned家系中的每位患者均存在PITX2基因第5外顯子第717-720位ACTT四個堿基的雜合缺失,導致該基因的讀碼框移位,蛋白質大段功能域缺失,而家系中正常人不存在此突變。

當前第31頁\共有95頁\編于星期六\2點PITX2基因的特征1996年定位克隆得到同源盒(homeobox)基因PITX2，編碼一種轉錄因子，屬于paired-bicoid基因家族，在發(fā)育中高度保守，cDNA編碼區(qū)與小鼠的同源基因91％相同，蛋白質的homeobox區(qū)100％相同。Paired-bicoid的標志是在同源結構域(homeodomain)

第3螺旋50位有一賴氨酸殘基，這一殘基識別TAAT盒后的CC序列。小鼠Pitx2參與牙胚的定位，在牙齒發(fā)育的較早階段表達于口腔上皮組織。Pitx2-/-

的小鼠牙胚的發(fā)育停止在蕾狀期。Pitx2還是心臟形態(tài)，上下頜骨的前突，垂體發(fā)育所必需的。當前第32頁\共有95頁\編于星期六\2點PITX2

基因結構圖當前第33頁\共有95頁\編于星期六\2點PITX2的重要功能域PITX2基因的各種變異剪切體均含相同的homeobox結構域(HD)和C末端，但是N端由不同的外顯子組成。對PITX2分子C端功能的研究提示C端能抑制DNA的結合從而為PITX2與協(xié)同因子Pit-1作用創(chuàng)造條件。當前第34頁\共有95頁\編于星期六\2點PITX2突變譜的總結15/23的突變發(fā)生在HD，7/23的突變發(fā)生在HD的3’編碼區(qū)。圖中矩形表示PITX2基因的外顯子，標出了翻譯的起始（ATG）及終止（TGA）位點。矩形中黑色的區(qū)域表示基因的Homeobox結構域。圖中的紅色星形、三角形、橢圓、圓形、箭頭依次表示不同的突變類型：剪切位點突變、缺失突變、點突變、無義突變及插入突變。

當前第35頁\共有95頁\編于星期六\2點PITX2突變功能研究T68P位于HD第2個螺旋，該突變不改變蛋白質對DNA結合功能，但是使之失去調節(jié)基因轉錄的功能；L54Q位于HD的第1個螺旋，該突變使蛋白質的穩(wěn)定性喪失；K88E恰改變HD的第50位賴氨酸，不僅使蛋白質喪失功能，并且抑制野生型蛋白正常功能的行使；V45L位于HD的第1個螺旋，該突變僅輕微降低DNA結合活性，但是能夠大幅上調突變蛋白的轉錄活性。當前第36頁\共有95頁\編于星期六\2點PITX2突變類型與臨床表型的關系不同類型的突變在臨床表型上存在差異。Kozlowski等針對與不同臨床表型相關的5種PITX2突變的功能研究表明，當突變蛋白還擁有部分功能時臨床的表型也較輕。Espinoza等的實驗也證實沒有牙齒異常表型的突變R84W與PITX2調控基因Dlx2啟動子的結合能力與野生型相似，而含有所有臨床表型的突變T68P則無法調節(jié)Dlx2的表達。當前第37頁\共有95頁\編于星期六\2點本研究中PITX2基因突變示意圖13898228248271

NCOARHD野生型突變型14482NCACTTDel突變位于HD的起始部位，移除大段重要功能域，所引起的臨床表型，特別是牙齒的缺失是目前所有報道中最嚴重的NovelIdentificationofaFour-base-pairDeletionMutationinPITX2inaRiegerSyndromeFamilyJDentRes82(12):1008-1012,2003當前第38頁\共有95頁\編于星期六\2點幾種特殊的突變類型5’調控區(qū)的突變三核苷酸重復次數突變與miRNA相關的突變當前第39頁\共有95頁\編于星期六\2點.Mutationsin5’regulatoryregionSelectiveToothAgenesis(STHAG),isthecommongeneralizedtermusedtodescribecongenitallymissingteethandisoneofthemostfrequentdevelopmentalanomaliesinhumans.Geneticlinkagestudiesonnon-syndromichypodontiahavesofaridentifiedfourgenesunderlyingthiscondition:MSX1,PAX9,WNT10AandAXIN2STHAG3(OMIM#604625)iscausedbyheterozygousmutationinthePAX9geneonchr14q12-13,whichcodesatranscriptionfactor,andessentialfortheswitchinodontogenicpotentialfromtheepitheliumtothemesenchyme,areexpressedinthedentalmesenchymeattheinitiationstageoftoothdevelopment當前第40頁\共有95頁\編于星期六\2點AfamilywithHypodontia當前第41頁\共有95頁\編于星期六\2點PedigreeoffamilyDEN29withhaplotypesforaSNPwithin(rs28933972)andmicrosatellitemarkers(D14SA1462,D14S1463,D14S1464)nearthePAX9locus.Theshadedhaplotypeisthatsegregatingwiththehypodontiaphenotype.當前第42頁\共有95頁\編于星期六\2點Anovelg.-1258G>AmutationinaconservedputativeregulatoryelementofPAX9isassociatedwithautosomaldominantmolarhypodontiaClinGenet2011:80:265–72當前第43頁\共有95頁\編于星期六\2點Multiple-speciescomparisonofa60bpsegmentbearingtheg.-1258G>Avariantidentifiedbythearrow當前第44頁\共有95頁\編于星期六\2點Microsatellite-expansiondiseasesaclassofneurologicalandneuromusculardisorderscausedbytheexpansionofshortstretchesofrepetitiveDNA(e.g.GGGGCC,CAG,CTG...)withinthehumangenome.akindofmutationwheremicrosatelliterepeatsincertaingenesexceedingthenormal,stable,threshold,whichdifferspergene.當前第45頁\共有95頁\編于星期六\2點NatureReviewsGenetics2010Vol11786-99當前第46頁\共有95頁\編于星期六\2點HuntingtonDisease(HD)ClinicalClassificationMovement/Cognitive/PsychiatricdisorderMeanonsetage35-55years.PrevalenceIncidence>1in10,000.GeneticTestingDiagnosticPresymptomatic–counsellingprotocol.當前第47頁\共有95頁\編于星期六\2點HuntingtonDisease(HD)Physicalfeatures:

-involuntarymovements -weightloss-abnormalgait-speech&swallowingdifficulties.PsychiatricManifestations: -personalitychanges -depression-aggression

-earlyonsetdementia.當前第48頁\共有95頁\編于星期六\2點GeneticaspectsofHuntingtondiseaseInheritanceADChromosomelocus4p16.3TrinucleotiderepeatCAGin5’translatedregionRepeatsizesNormal≤26Mutable27-35Reducedpenetrance36-39Fullypenetrant≥40ProteinproductHuntingtinEarlyonsetformJuvenilePaternallytransmitted當前第49頁\共有95頁\編于星期六\2點Dynamicmutations(動態(tài)突變):Mutationsinsomedisordersinvolveamplificationoftrinucleotiderepeatsequencesduringgametogenesis.

Becomemutatedthroughatwo-stepprocess.Thefirstmutation,calledthe'premutation',doesn'tcauseanyclinicalsymptoms.Asecondmutationwasrequiredtoconvertthe'premutation'intoa'fullmutation'capableofcausingtheclinicalsymptoms

當前第50頁\共有95頁\編于星期六\2點StructureoftheHuntingtondiseasegene.Shortverticalbarsrepresentexons.當前第51頁\共有95頁\編于星期六\2點Huntingtondisease-atripletrepeatdiseaseCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG…...CAG11-35CAGtripletrepeatsarenormal:encodesarunof11-35glutamineaminoacidresiduesintheprotein.Arunof>35glutamineresiduescausestheproteintoaggregateinthebraincellsandcauseprogressivecelldeath.Runsof>35CAGrepeatsintheHDgeneexpandfurther(particularlyduringmalemeiosis)causingearlierageofonsetinchildrenofmenwhohavethegene–anticipation.normalbrainHDpatientbrain當前第52頁\共有95頁\編于星期六\2點Mechanismsofpathogenesisformicrosatelliteinstabilitydisorders.當前第53頁\共有95頁\編于星期六\2點Cont.Mechanismsofpathogenesisformicrosatelliteinstabilitydisorders.DNARepairVol7(2008)1135–54當前第54頁\共有95頁\編于星期六\2點Repeatassociatednon-ATG(RAN)translation:newstartsinmicrosatelliteexpansiondisorders.CurrentOpinioninGenetics&Development2014,26:6–15當前第55頁\共有95頁\編于星期六\2點EpigeneticmodificationsassociatedwithTNRexpansiondiseasesTrendsinMolecularMedicine2013,Vol.19,No.11：655-663Epigeneticmodificationsintrinucleotiderepeatdiseases當前第56頁\共有95頁\編于星期六\2點microRNAandsinglegenedisorders當前第57頁\共有95頁\編于星期六\2點OriginalcausalmechanismsmiRNAasacandidategeneofthediseaseMutationorSNP(alsoreferredtoasmiRSNP)islocatedinthemiRNA-bindingsite,ornearbySuccesiveeffectsofmutatedproteinsMechanismsinvolvingmicroRNAininheriteddiseases當前第58頁\共有95頁\編于星期六\2點ClinGenet2010:77:306–313當前第59頁\共有95頁\編于星期六\2點#613074DEAFNESS,AUTOSOMALDOMINANT50;DFNA50mappedthephenotypetochromosome7q32,causedbymutationsinamicroRNA,miR-96

ThiswasthefirststudytoimplicateamiRNAinamendeliandisorderMutationsintheseedregionofhumanmiR-96areresponsiblefornonsyndromicprogressivehearingloss.NatureGenet.41:609-613,2009miRNAasacandidategeneofthedisease當前第60頁\共有95頁\編于星期六\2點SequenceanalysisexcludedUBE2H,SMO,ATP6V1F,CALU,CCDC136,TSPAN33,KLHDC10,C7ORF68,FLNC,IMPDH1andMIR129-1.AsetofthreegenesencodingmiRNAs(MIR96,MIR182andMIR183)wasannotatedwithintheinterval.Theyaretranscribedasasinglepolycistronictranscriptandwerereportedtobeexpressedintheinnerear當前第61頁\共有95頁\編于星期六\2點.MutationsintheseedregionofMIR96causeDFNA50hearingloss.(a)PedigreesoftheSpanishfamilies(family1,top;2,bottom)segregatingDFNA50hearingloss.(b)Electropherogramsdepictthe23-ntmaturesequenceofhumanmiR-96.Thenucleotidescorrespondingtotheseedregionareboxed.當前第62頁\共有95頁\編于星期六\2點Predictedsecondarystructureandprocessingofthewild-typeandmutantformsofmiR96.當前第63頁\共有95頁\編于星期六\2點DownregulationofpredictedprimarytargetsisimpairedbythemiR-96(+13G>A)and(+14C>A)mutations.當前第64頁\共有95頁\編于星期六\2點LewisMA,QuintE,GlazierAMetal.AnENU-inducedmutationofmiR-96associatedwithprogressivehearinglossinmice.NatGenet2009:41:614–618.Amousemutantpresentedaphenotypesimilartothehumandisease,whichcarriesa(A>T)basesubstitutionintheseedsequenceofmiR-96.當前第65頁\共有95頁\編于星期六\2點SequenceVariantsinSLITRK1AreAssociatedwithTourette’sSyndromeScience2005：310,317-320Thesingle-basechangemapstothe3‘UTRoftheSLITRK1

transcriptandcorrespondstoahighlyconservednucleotidewithinthepredictedbindingsiteforthehumanmiRNAhsa-miR-189MutationorSNP(alsoreferredtoasmiRSNP)islocatedinthemiRNA-bindingsite,ornearby當前第66頁\共有95頁\編于星期六\2點當前第67頁\共有95頁\編于星期六\2點MutationsarelocatedinapredictedtargetsiteformiR-140andinapredictedtargetsiteformiR-691withinthe3’UTRofREEP1.當前第68頁\共有95頁\編于星期六\2點MutationsinthenovelmitochondrialproteinREEP1causehereditaryspasticparaplegiatype31.AmJHumGenet2006:79:365–369.當前第69頁\共有95頁\編于星期六\2點BeetzC,SchuleR,DeconinckTetal.REEP1mutationspectrumandgenotype/phenotypecorrelationinhereditaryspasticparaplegiatype31.Brain2008:131:1078–1086當前第70頁\共有95頁\編于星期六\2點Thecomplexityofmodifyingfactorsforphenotypesofsinglegenedisorderscis-andtrans-actingfactorsepigeneticfactorsproteinsbelongingtothesamepathwayornetworkproteinsinvolvedinstand-alonepathwaysbutconvergingonacommonfinalpathwayorendinginthesamebiologicalfunctionextrinsicnon-geneticorenvironmentalfactors.當前第71頁\共有95頁\編于星期六\2點同一信號轉導通路的不同基因發(fā)生突變的同類疾病TheRASopathies:developmentalsyndromesofRas/MAPKpathwaydysregulationCurrentOpinioninGenetics&Development2009,19:230–236當前第72頁\共有95頁\編于星期六\2點Ras/mitogen-activatedproteinkinase(MAPK)pathwayPlaysanessentialroleinthecontrolofthecellcycleanddifferentiationItsdysregulationhasprofounddevelopmentalconsequences.當前第73頁\共有95頁\編于星期六\2點當前第74頁\共有95頁\編于星期六\2點Each‘RASopathies’eachexhibituniquephenotypicfeaturesManysharecharacteristicoverlappingfeaturesCraniofacialdysmorphologyCardiacmalformationsCutaneous,musculoskeletalandocularabnormalities,VaryingdegreesofneurocognitiveimpairmentInsomesyndromes,anincreasedriskofdevelopingcancer.當前第75頁\共有95頁\編于星期六\2點當前第76頁\共有95頁\編于星期六\2點OutcomesofmutationsThevastmajorityofthesemutationsresultinincreasedsignaltransductiondowntheRas/MAPKpathwayUsuallytoalesserextentthansomaticmutationsassociatedwithoncogenesis.Itislikelythatthestronglyactivatingoncogenicmutationscannotbetoleratedasgermlinemutations.ThemostcommononcogenicBRAFmutation,V600E,doesnotoccurinCFCsyndromeThespecificKRASmutationsassociatedwithNSarenotthesameastheknownsomaticmutationsassociatedwithcancer.當前第77頁\共有95頁\編于星期六\2點Kinasopathy

.Aclinicalphenotypethatis

causedbygermlinemutations

inthekinasedomainof

functionalproteinsthatlead

toaloss-of-functionor

gain-of-functionoftheproteinKinasemutationsinhumandisease:

interpretinggenotype–phenotype

relationshipsNatureReviewsGenetics2010Vol1160-74同類功能分子的不同基因的突變導致的疾病當前第78頁\共有95頁\編于星期六\2點當前第79頁\共有95頁\編于星期六\2點當前第80頁\共有95頁\編于星期六\2點當前第81頁\共有95頁\編于星期六\2點Thecharactersofmutationalhotspotsassociatedkinasestructures

CommonneutralmutationstendtooccupytheC-terminalregionsofthecatalyticcoreandsubstrate-bindingorcatalyticresiduesareavoided.Inheritedgermlinediseasecausingmutations,mostofwhichresultinloss-offunctiondevelopmentaland/ormetabolicdisorders,tendtoclusterinregionsofthecatalyticcoreinvolvedinregulationandsubstratebinding,especiallyresiduesthatparticipateinprotein–proteinandallostericinteractions.AcquiredsomaticmutationsthatcauseorcontributetocancertendtopopulateATPbindingandcatalyticresidues.當前第82頁\共有95頁\編于星期六\2點CisandtransregulationofSMN1andSMN2splicinganditsimpactontranslation.Howgeneticmodif