单基因遗传病高级遗传

Etiologyofdiseases.Foranyconditiontheoverallbalanceofgeneticandenvironmentaldeterminantscanberepresentedbyapointsomewherewithinthetriangle.ClassificationofGeneticDisordersSinglegenedisordersarecausedbydefectsinoneparticulargene,andoftenhavesimpleandpredictableinheritancepatterns.Theyaffectabout1percentofthepopulationasawhole.Epigeneticmodifications？Otherreasons?目前一页\总数九十五页\编于十点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)目前二页\总数九十五页\编于十点Singlegenedisorders:disordersinwhichinheritanceisduetoasinglemutantgeneMendelianinheritanceGenesareunitsofheredity,basedinDNAPhenotype(physicalorfunctionalabnormalities)Genotype(DNAchange)4.AutosomalvsX-linked

determinedbywhethertheresponsiblegeneiscarriedononeoftheautosomalchromosomesorontheXchromosome5.DominantvsRecessive,basedonphenotypicexpression目前三页\总数九十五页\编于十点RecessiveHomozygoteswithtwocopiesofthealteredgeneareaffectedDominantHeterozygoteswithonecopyofthealteredgeneareaffectedX-linkedrecessiveMaleswithonecopyofthealteredgeneontheX-chromosomeareaffectedMale目前四页\总数九十五页\编于十点Singlegenedisorders -Highriskstorelatives

-Dominant/recessivepedigreepatterns

-Someisolatedcasesduetonewdominantmutations

-Structuralproteins,enzymes,receptors,transcriptionfactorsI:1I:2II:1II:2II:3II:5II:6II:8III:1III:2IV:11212341ⅠⅡⅢ目前五页\总数九十五页\编于十点目前六页\总数九十五页\编于十点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目前七页\总数九十五页\编于十点

CharacteristicsofAutosomalDominantinheritance

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

目前八页\总数九十五页\编于十点

Autosomaldominanceinheritance

(AD)Pedigreeshowingtypicalinheritanceofaformofprogressivesensorineuraldeafness(DFNA1)inheritedasanautosomaldominanttrait目前九页\总数九十五页\编于十点

CharacteristicsofAutosomalRecessiveInheritance

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

2.bothsexesareaffectedwithequalfrequencyataratioof1:1

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

目前十页\总数九十五页\编于十点

AutosomalRecessiveInheritance

(AR)

目前十一页\总数九十五页\编于十点

CharacteristicsofX-linkedDominantInheritance

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

3.BothmaleandfemaleoffspringofAffectedfemalehavea50percentriskofinheritingthephenotype.

4.Thepedigreepatternisthesameasautosomaldominantinheritance.

目前十二页\总数九十五页\编于十点

X-linkedDominantInheritance

(XD)目前十三页\总数九十五页\编于十点

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

Thegenemaybetransmittedthroughaseriesofcarrierfemales;affectedmalesinheritthemutantallelefromthemotheronlyHeterozygousfemalesareusuallyunaffected,butsomemayexpresstheconditionwithvariableseverityasdeterminedbythepatternofXinactivation目前十四页\总数九十五页\编于十点

X-linked

RecessiveInheritance

(XR)目前十五页\总数九十五页\编于十点Y-linkedinheritance

Gene:YA（mutantallele

）

YaGenotype:XYA

XYaholandricinheritance(全男性遗传)male-to-male目前十六页\总数九十五页\编于十点

Y-linkedinheritance

目前十七页\总数九十五页\编于十点SinglegenedisordersHuntingtonDiseaseMyotonicDystrophyHereditaryMotorSensoryNeuropathy(HMSN)NeurofibromatosisMarfansyndromeCysticFibrosisSpinalMuscularAtrophy(SMA)DuchenneMuscularDystrophyHemophilia目前十八页\总数九十五页\编于十点Somaticmosaicismandsinglegenedisorders目前十九页\总数九十五页\编于十点Mosaicism:referstoamixtureofcellsofdifferentgeneticcompositioninoneindividual.Whenthegenotypeofonezygoteisalteredbychromosomalmis-segregationorDNAmutationinadetectablenumberofcells,itisusuallycalled‘‘mosaicism’’.Dependingonthedisorderandtheclassofmutation,ingenesforwhichtherearesufficientnumbersofpatientsstudied,6–20%ofcasesareduetosomaticmutation.Theclassesofmutation:basepairchanges,insertions/deletion(indels),shorttandemrepeatmutations,copynumbervariants(CNVs),transposon-mediatedmutations.目前二十页\总数九十五页\编于十点ExamplesofconfirmedsomaticmosaicismNeurofibromatosis1and2McCune-AlbrightsyndromeParoxysmalnocturnalhemoglobinuria(PNH)andotherdisordersdetectableinseparatedbloodcellsIncontinentiapigmentiinmalesandotherdermalandretinalexamplesofsomaticmosaicismSomaticmosaicismintheheartandkidneyMutationsinGJA5inthecardiacDNAofpatientswithatrialfibrillationAlportssyndromeinkidneySomaticmosaicismoftheneuromuscularsystemX-linkedPeriventricularheterotopiaSubcorticalbandheterotopiaSomaticmosaicismindysmorphicsyndromesTownes-BrockssyndromeCamptomelicDysplasia目前二十一页\总数九十五页\编于十点Combinedgerm-lineandsomaticmosaicismMutationResearch705(2010)96–106目前二十二页\总数九十五页\编于十点PaternalAgeEffect(PAE)andsinglegenedisordersTherearecertaindenovogermlinemutationsassociatedwithgeneticdisorderswhosemutationratespergenerationareordersofmagnitudehigherthanthegenomeaverage.Moreover,thesemutationsoccurexclusivelyinthemalegermlineandoldermenhaveahigherprobabilityofhavinganaffectedchildthanyoungerones.TheclassicexampleofageneticdisorderexhibitingaPAEisachondroplasia,causedpredominantlybyasingle-nucleotidesubstitution(c.1138G>A)inFGFR3.

Possibleexplanation:Mutantspermatogonialstemcellshaveaproliferativeadvantageoverunmutatedcells.

HumanMolecularGenetics,2013,Vol.22,No.204117–4126目前二十三页\总数九十五页\编于十点目前二十四页\总数九十五页\编于十点目前二十五页\总数九十五页\编于十点如何确定所研究的疾病是单基因病？确认方法主要有以下两种：1)参考OMIM(OnlineMendelianInheritanceinMan)数据库，根据疾病的表型或者临床症状等确定是否属于OMIM收录的单基因病。OMIM除了简略描述各种疾病的临床特征、诊断、鉴别诊断、治疗与预防外，还提供已知相关致病基因的连锁关系、染色体定位、组成结构和功能、动物模型等资料，并附有经缜密筛选的相关参考文献。网址为：2)绘制疾病的遗传系谱图，通过系谱图分析其遗传方式来判断是否属于孟德尔遗传病。系谱分析法是研究人类遗传规律的重要方法。在临床上，常用系谱分析法来判断某种疾病的遗传方式。系谱图就是从先证者（proband）（家系中第一个被医生确诊的某遗传病的患者，或者具有某种性状的成员）入手，追溯调查其所有家庭成员的数目、亲属关系、某种遗传病（或性状）的分布等资料，按照一定格式绘制而成的图解。目前二十六页\总数九十五页\编于十点单基因病研究举例及进展目前二十七页\总数九十五页\编于十点Rieger综合征(#MIM180500)致病基因PITX2的研究

Rieger综合征是Axenfeld-Rieger症候群中最为严重的一型典型临床表现：眼前节发育不良，继发青光眼口颌发育异常：先天多数牙缺失，过小牙，畸形牙面中部发育不足，下颌前突等脐残断回缩异常遗传方式：常染色体显性遗传，发生率约为1:200,000目前二十八页\总数九十五页\编于十点临床资料：家系I先证者目前二十九页\总数九十五页\编于十点Rieger综合征相关基因和染色体区域PITX2

4q25FOXC16p25PAX611p1313q14AlltheseRieger-syndrome-associatedgenes——encodetranscriptionfactorsandhavebeenshowntoplayimportantrolesinembryonicdevelopment目前三十页\总数九十五页\编于十点测序结果Wildtype1-III:4cloned1-III:4uncloned家系中的每位患者均存在PITX2基因第5外显子第717-720位ACTT四个碱基的杂合缺失,导致该基因的读码框移位,蛋白质大段功能域缺失,而家系中正常人不存在此突变。

目前三十一页\总数九十五页\编于十点PITX2基因的特征1996年定位克隆得到同源盒(homeobox)基因PITX2，编码一种转录因子，属于paired-bicoid基因家族，在发育中高度保守，cDNA编码区与小鼠的同源基因91％相同，蛋白质的homeobox区100％相同。Paired-bicoid的标志是在同源结构域(homeodomain)

第3螺旋50位有一赖氨酸残基，这一残基识别TAAT盒后的CC序列。小鼠Pitx2参与牙胚的定位，在牙齿发育的较早阶段表达于口腔上皮组织。Pitx2-/-

的小鼠牙胚的发育停止在蕾状期。Pitx2还是心脏形态，上下颌骨的前突，垂体发育所必需的。目前三十二页\总数九十五页\编于十点PITX2

基因结构图目前三十三页\总数九十五页\编于十点PITX2的重要功能域PITX2基因的各种变异剪切体均含相同的homeobox结构域(HD)和C末端，但是N端由不同的外显子组成。对PITX2分子C端功能的研究提示C端能抑制DNA的结合从而为PITX2与协同因子Pit-1作用创造条件。目前三十四页\总数九十五页\编于十点PITX2突变谱的总结15/23的突变发生在HD，7/23的突变发生在HD的3’编码区。图中矩形表示PITX2基因的外显子，标出了翻译的起始（ATG）及终止（TGA）位点。矩形中黑色的区域表示基因的Homeobox结构域。图中的红色星形、三角形、椭圆、圆形、箭头依次表示不同的突变类型：剪切位点突变、缺失突变、点突变、无义突变及插入突变。

目前三十五页\总数九十五页\编于十点PITX2突变功能研究T68P位于HD第2个螺旋，该突变不改变蛋白质对DNA结合功能，但是使之失去调节基因转录的功能；L54Q位于HD的第1个螺旋，该突变使蛋白质的稳定性丧失；K88E恰改变HD的第50位赖氨酸，不仅使蛋白质丧失功能，并且抑制野生型蛋白正常功能的行使；V45L位于HD的第1个螺旋，该突变仅轻微降低DNA结合活性，但是能够大幅上调突变蛋白的转录活性。目前三十六页\总数九十五页\编于十点PITX2突变类型与临床表型的关系不同类型的突变在临床表型上存在差异。Kozlowski等针对与不同临床表型相关的5种PITX2突变的功能研究表明，当突变蛋白还拥有部分功能时临床的表型也较轻。Espinoza等的实验也证实没有牙齿异常表型的突变R84W与PITX2调控基因Dlx2启动子的结合能力与野生型相似，而含有所有临床表型的突变T68P则无法调节Dlx2的表达。目前三十七页\总数九十五页\编于十点本研究中PITX2基因突变示意图13898228248271

NCOARHD野生型突变型14482NCACTTDel突变位于HD的起始部位，移除大段重要功能域，所引起的临床表型，特别是牙齿的缺失是目前所有报道中最严重的NovelIdentificationofaFour-base-pairDeletionMutationinPITX2inaRiegerSyndromeFamilyJDentRes82(12):1008-1012,2003目前三十八页\总数九十五页\编于十点几种特殊的突变类型5’调控区的突变三核苷酸重复次数突变与miRNA相关的突变目前三十九页\总数九十五页\编于十点.Mutationsin5’regulatoryregionSelectiveToothAgenesis(STHAG),isthecommongeneralizedtermusedtodescribecongenitallymissingteethandisoneofthemostfrequentdevelopmentalanomaliesinhumans.Geneticlinkagestudiesonnon-syndromichypodontiahavesofaridentifiedfourgenesunderlyingthiscondition:MSX1,PAX9,WNT10AandAXIN2STHAG3(OMIM#604625)iscausedbyheterozygousmutationinthePAX9geneonchr14q12-13,whichcodesatranscriptionfactor,andessentialfortheswitchinodontogenicpotentialfromtheepitheliumtothemesenchyme,areexpressedinthedentalmesenchymeattheinitiationstageoftoothdevelopment目前四十页\总数九十五页\编于十点AfamilywithHypodontia目前四十一页\总数九十五页\编于十点PedigreeoffamilyDEN29withhaplotypesforaSNPwithin(rs28933972)andmicrosatellitemarkers(D14SA1462,D14S1463,D14S1464)nearthePAX9locus.Theshadedhaplotypeisthatsegregatingwiththehypodontiaphenotype.目前四十二页\总数九十五页\编于十点Anovelg.-1258G>AmutationinaconservedputativeregulatoryelementofPAX9isassociatedwithautosomaldominantmolarhypodontiaClinGenet2011:80:265–72目前四十三页\总数九十五页\编于十点Multiple-speciescomparisonofa60bpsegmentbearingtheg.-1258G>Avariantidentifiedbythearrow目前四十四页\总数九十五页\编于十点Microsatellite-expansiondiseasesaclassofneurologicalandneuromusculardisorderscausedbytheexpansionofshortstretchesofrepetitiveDNA(e.g.GGGGCC,CAG,CTG...)withinthehumangenome.akindofmutationwheremicrosatelliterepeatsincertaingenesexceedingthenormal,stable,threshold,whichdifferspergene.目前四十五页\总数九十五页\编于十点NatureReviewsGenetics2010Vol11786-99目前四十六页\总数九十五页\编于十点HuntingtonDisease(HD)ClinicalClassificationMovement/Cognitive/PsychiatricdisorderMeanonsetage35-55years.PrevalenceIncidence>1in10,000.GeneticTestingDiagnosticPresymptomatic–counsellingprotocol.目前四十七页\总数九十五页\编于十点HuntingtonDisease(HD)Physicalfeatures:

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

-earlyonsetdementia.目前四十八页\总数九十五页\编于十点GeneticaspectsofHuntingtondiseaseInheritanceADChromosomelocus4p16.3TrinucleotiderepeatCAGin5’translatedregionRepeatsizesNormal≤26Mutable27-35Reducedpenetrance36-39Fullypenetrant≥40ProteinproductHuntingtinEarlyonsetformJuvenilePaternallytransmitted目前四十九页\总数九十五页\编于十点Dynamicmutations(动态突变):Mutationsinsomedisordersinvolveamplificationoftrinucleotiderepeatsequencesduringgametogenesis.

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

目前五十页\总数九十五页\编于十点StructureoftheHuntingtondiseasegene.Shortverticalbarsrepresentexons.目前五十一页\总数九十五页\编于十点Huntingtondisease-atripletrepeatdiseaseCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG…...CAG11-35CAGtripletrepeatsarenormal:encodesarunof11-35glutamineaminoacidresiduesintheprotein.Arunof>35glutamineresiduescausestheproteintoaggregateinthebraincellsandcauseprogressivecelldeath.Runsof>35CAGrepeatsintheHDgeneexpandfurther(particularlyduringmalemeiosis)causingearlierageofonsetinchildrenofmenwhohavethegene–anticipation.normalbrainHDpatientbrain目前五十二页\总数九十五页\编于十点Mechanismsofpathogenesisformicrosatelliteinstabilitydisorders.目前五十三页\总数九十五页\编于十点Cont.Mechanismsofpathogenesisformicrosatelliteinstabilitydisorders.DNARepairVol7(2008)1135–54目前五十四页\总数九十五页\编于十点Repeatassociatednon-ATG(RAN)translation:newstartsinmicrosatelliteexpansiondisorders.CurrentOpinioninGenetics&Development2014,26:6–15目前五十五页\总数九十五页\编于十点EpigeneticmodificationsassociatedwithTNRexpansiondiseasesTrendsinMolecularMedicine2013,Vol.19,No.11：655-663Epigeneticmodificationsintrinucleotiderepeatdiseases目前五十六页\总数九十五页\编于十点microRNAandsinglegenedisorders目前五十七页\总数九十五页\编于十点OriginalcausalmechanismsmiRNAasacandidategeneofthediseaseMutationorSNP(alsoreferredtoasmiRSNP)islocatedinthemiRNA-bindingsite,ornearbySuccesiveeffectsofmutatedproteinsMechanismsinvolvingmicroRNAininheriteddiseases目前五十八页\总数九十五页\编于十点ClinGenet2010:77:306–313目前五十九页\总数九十五页\编于十点#613074DEAFNESS,AUTOSOMALDOMINANT50;DFNA50mappedthephenotypetochromosome7q32,causedbymutationsinamicroRNA,miR-96

ThiswasthefirststudytoimplicateamiRNAinamendeliandisorderMutationsintheseedregionofhumanmiR-96areresponsiblefornonsyndromicprogressivehearingloss.NatureGenet.41:609-613,2009miRNAasacandidategeneofthedisease目前六十页\总数九十五页\编于十点SequenceanalysisexcludedUBE2H,SMO,ATP6V1F,CALU,CCDC136,TSPAN33,KLHDC10,C7ORF68,FLNC,IMPDH1andMIR129-1.AsetofthreegenesencodingmiRNAs(MIR96,MIR182andMIR183)wasannotatedwithintheinterval.Theyaretranscribedasasinglepolycistronictranscriptandwerereportedtobeexpressedintheinnerear目前六十一页\总数九十五页\编于十点.MutationsintheseedregionofMIR96causeDFNA50hearingloss.(a)PedigreesoftheSpanishfamilies(family1,top;2,bottom)segregatingDFNA50hearingloss.(b)Electropherogramsdepictthe23-ntmaturesequenceofhumanmiR-96.Thenucleotidescorrespondingtotheseedregionareboxed.目前六十二页\总数九十五页\编于十点Predictedsecondarystructureandprocessingofthewild-typeandmutantformsofmiR96.目前六十三页\总数九十五页\编于十点DownregulationofpredictedprimarytargetsisimpairedbythemiR-96(+13G>A)and(+14C>A)mutations.目前六十四页\总数九十五页\编于十点LewisMA,QuintE,GlazierAMetal.AnENU-inducedmutationofmiR-96associatedwithprogressivehearinglossinmice.NatGenet2009:41:614–618.Amousemutantpresentedaphenotypesimilartothehumandisease,whichcarriesa(A>T)basesubstitutionintheseedsequenceofmiR-96.目前六十五页\总数九十五页\编于十点SequenceVariantsinSLITRK1AreAssociatedwithTourette’sSyndromeScience2005：310,317-320Thesingle-basechangemapstothe3‘UTRoftheSLITRK1

transcriptandcorrespondstoahighlyconservednucleotidewithinthepredictedbindingsiteforthehumanmiRNAhsa-miR-189MutationorSNP(alsoreferredtoasmiRSNP)islocatedinthemiRNA-bindingsite,ornearby目前六十六页\总数九十五页\编于十点目前六十七页\总数九十五页\编于十点MutationsarelocatedinapredictedtargetsiteformiR-140andinapredictedtargetsiteformiR-691withinthe3’UTRofREEP1.目前六十八页\总数九十五页\编于十点MutationsinthenovelmitochondrialproteinREEP1causehereditaryspasticparaplegiatype31.AmJHumGenet2006:79:365–369.目前六十九页\总数九十五页\编于十点BeetzC,SchuleR,DeconinckTetal.REEP1mutationspectrumandgenotype/phenotypecorrelationinhereditaryspasticparaplegiatype31.Brain2008:131:1078–1086目前七十页\总数九十五页\编于十点Thecomplexityofmodifyingfactorsforphenotypesofsinglegenedisorderscis-andtrans-actingfactorsepigeneticfactorsproteinsbelongingtothesamepathwayornetworkproteinsinvolvedinstand-alonepathwaysbutconvergingonacommonfinalpathwayorendinginthesamebiologicalfunctionextrinsicnon-geneticorenvironmentalfactors.目前七十一页\总数九十五页\编于十点同一信号转导通路的不同基因发生突变的同类疾病TheRASopathies:developmentalsyndromesofRas/MAPKpathwaydysregulationCurrentOpinioninGenetics&Development2009,19:230–236目前七十二页\总数九十五页\编于十点Ras/mitogen-activatedproteinkinase(MAPK)pathwayPlaysanessentialroleinthecontrolofthecellcycleanddifferentiationItsdysregulationhasprofounddevelopmentalconsequences.目前七十三页\总数九十五页\编于十点目前七十四页\总数九十五页\编于十点Each‘RASopathies’eachexhibituniquephenotypicfeaturesManysharecharacteristicoverlappingfeaturesCraniofacialdysmorphologyCardiacmalformationsCutaneous,musculoskeletalandocularabnormalities,VaryingdegreesofneurocognitiveimpairmentInsomesyndromes,anincreasedriskofdevelopingcancer.目前七十五页\总数九十五页\编于十点目前七十六页\总数九十五页\编于十点OutcomesofmutationsThevastmajorityofthesemutationsresultinincreasedsignaltransductiondowntheRas/MAPKpathwayUsuallytoalesserextentthansomaticmutationsassociatedwithoncogenesis.Itislikelythatthestronglyactivatingoncogenicmutationscannotbetoleratedasgermlinemutations.ThemostcommononcogenicBRAFmutation,V600E,doesnotoccurinCFCsyndromeThespecificKRASmutationsassociatedwithNSarenotthesameastheknownsomaticmutationsassociatedwithcancer.目前七十七页\总数九十五页\编于十点Kinasopathy

.Aclinicalphenotypethatis

causedbygermlinemutations

inthekinasedomainof

functionalproteinsthatlead

toaloss-of-functionor

gain-of-functionoftheproteinKinasemutationsinhumandisease:

interpretinggenotype–phenotype

relationshipsNatureReviewsGenetics2010Vol1160-74同类功能分子的不同基因的突变导致的疾病目前七十八页\总数九十五页\编于十点目前七十九页\总数九十五页\编于十点目前八十页\总数九十五页\编于十点目前八十一页\总数九十五页\编于十点Thecharactersofmutationalhotspotsassociatedkinasestructures

CommonneutralmutationstendtooccupytheC-terminalregionsofthecatalyticcoreandsubstrate-bindingorcatalyticresiduesareavoided.Inheritedgermlinediseasecausingmutations,mostofwhichresultinloss-offunctiondevelopmentaland/ormetabolicdisorders,tendtoclusterinregionsofthecatalyticcoreinvolvedinregulationandsubstratebinding,especiallyresiduesthatparticipateinprotein–proteinandallostericinteractions.AcquiredsomaticmutationsthatcauseorcontributetocancertendtopopulateATPbindingandcatalyticresidues.目前八十二页\总数九十五页\编于十点CisandtransregulationofSMN1andSMN2splicinganditsimpactontranslation.Howgene