疾病的单基因遗传PPT课件.ppt

03疾病的单基因遗传MonogenicInheritance 1 single genedisorderormonogenicdisorderSomedisordersresultwhenamutationcausestheproductofasinglegenetobealteredormissing ThesedisordersareinheritedinsimplepatternssimilartooridenticalwiththosedescribedbyMendelforcertaindiscretecharacteristicsingardenpeas Therefore it salsocalledMendeliandiseases 2 3 病例分析 姓名 不幸 男性 69岁 已3次经中南大学湘雅二医院临床确诊异时性结直肠癌 即52岁时诊断为右半结肠癌 61岁发生乙状结肠癌 68岁患直肠癌 家族史 先证者的儿子于25岁和37岁两次诊断为异时性结直肠癌 其家族4代31人中有17人共21例次诊断结直肠癌等恶性肿瘤 其中12名 70 6 患者患有结直肠癌 另6名患者发现结直肠外恶性肿瘤 包括子宫内膜 胃 脑 肝脏等 所有患者恶性肿瘤的平均发病年龄是41岁 结直肠癌的平均发病年龄是42 9岁 患者的男女性别比例是10 7 3 1 PedigreeandProband Humansareuniqueamongorganismsinmanyways butonewaywhichisnearanddeartoageneticist sheartisthathumansarenotsusceptibletogeneticexperimentation 4 ThestudyofinheritedMendeliantraitsinhumansmustrelyonobservationsmadewhileworkingwithindividualfamilies 5 ClassicalcrossfertilizationbreedingexperimentsasperformedbyMendelarenotallowedinhumans Humangeneticistsarenotallowedtoselectivelybreedforthetraitstheywishtostudy 6 Oneofmostpowerfultoolsinhumangeneticstudiesispedigreeanalysis 7 pedigreeTheyaregraphicrepresentationsofafamilytreewhichshowthebiologicalrelationshipoftheindexcase orprobandorpropositustotherestoftheindividuals Afamilytreediagramthatshowshowaparticulargenetictraitordiseasehasbeeninherited 8 Whenhumangeneticistsfirstbegantopublishfamilystudies theyusedavarietyofsymbolsandconventions Nowthereareagreeduponstandardsfortheconstructionofpedigrees 9 Symbols 10 11 12 调查资料绘制系谱 家族史 先证者的儿子于25岁和37岁两次诊断为异时性结直肠癌 其家族4代31人中有17人共21例次诊断结直肠癌等恶性肿瘤 其中12名 70 6 患者患有结直肠癌 另6名患者发现结直肠外恶性肿瘤 包括子宫内膜 胃 脑 肝脏等 所有患者恶性肿瘤的平均发病年龄是41岁 结直肠癌的平均发病年龄是42 9岁 患者的男女性别比例是10 7 12 13 14 判断遗传性非息肉性结直肠癌的阿姆斯特丹I标准 家族中至少有3例组织病理学证实的结直肠癌患者 其中1例是另外2例的一级亲属 至少有连续两代人发生结直肠癌 至少有1例患者是在50岁之前发病 排除家族性腺瘤性息肉病 结直肠癌是一种最常见的内脏恶性肿瘤 发病率较高 其中大约有15 20 为家族性发病 如家族性腺瘤息肉 Familialadenomatouspolyposis FAP 和遗传性非息肉性结直肠癌 Hereditarynonpolyposiscolorectalcancer HNPCC 寻找致病基因及致病突变 14 遗传性非息肉性结直肠癌 HNPCC 的发生与DNA错配修复缺陷有关 已知至少有5种错配修复 mismatchrepair MMR 基因 MSH2 MLH1 MSH6 PMS1和PMS2 与其有关 目前已在HNPCC患者中发现了400多种MMR基因的突变 其中MSH2基因突变约占50 MLH1基因突变约占39 15 MSH2和MLH1基因筛查 15 通过PCR扩增和序列测定 在先证者gDNA中发现了MSH2基因7号外显子中的一种国内外尚未见报道的新突变 该突变由于4个核苷酸 CCGA 的插入导致该4个核苷酸重复 MSH2 c 1215 1218dupCCGA 形成移码突变 产生异常截短蛋白 所有被检测的患者均发现该突变 表型正常的成年家系成员均正常 另外 50个家系外正常对照中未发现该基因突变 我们确认该突变导致了该家系的遗传性非息肉性结直肠癌的发生 16 16 17 症状前诊断 家系中1人 IV 1 为突变基因携带者 该携带者 IV 1 年仅16岁 由于年龄尚小 尚未到发病年龄 目前未检出结直肠癌或其他癌症 但应引起高度重视 17 MSH2mutation 遗传性非息肉性结直肠癌 Autosomaldominantinheritance 18 2 Autosomaldominantinheritance ThepatternofautosomaldominantinheritanceisperhapstheeasiesttypeofMendelianinheritancetorecognizeinapedigree Onedoseofthemutantgene onemutantallele isallthatisrequiredfortheexpressionofthephenotype 19 Therearethreereasonswhyanindividualwithanautosomaldominantdiseaseshouldalwaysbeconsideredasbeingaheterozygoteuntilprovenotherwise homozygotes heterozygotes 20 Supposeafatherisheterozygousforanautosomaldominantgene withalleleD themutantdominantallele andalleled therecessivenormalallele Hecanproducetwotypesofgametes Dandd Supposealsohiswifeishomozygousnormal havingbothdalleles ThePunnettSquareisconstructedasfollows 21 Onegametecomesfromeachparenttoproducethegenotypeoftheoffspring Twooutofthefourpossiblecombinationsareaffected twooutoffourarenormal 22 SamplePedigree 23 Withtheunderstandingthatalmostallaffectedindividualsareheterozygotes andthatinmostmatingsinvolvingapersonwithanautosomaldominanttraittheotherpartnerwillbehomozygousnormal therearefourhallmarksofautosomaldominantinheritance 24 Therearefourhallmarksofautosomaldominantinheritance 1 Exceptfornewmutations whicharerareinnatureandextremelyrareonexaminationpedigrees andthecomplexitiesofincompletepenetrancetobediscussedlater everyaffectedindividualhasanaffectedbiologicalparent Thereisnoskippingofgenerations 2 Malesandfemaleshaveanequallylikelychanceofinheritingthemutantalleleandbeingaffected Therecurrenceriskofeachchildofanaffectedparentis1 2 25 3 Normalsiblingsofaffectedindividualsdonottransmitthetraittotheiroffspring 4 Thedefectiveproductofthegeneisusuallyastructuralprotein notanenzyme Structuralproteinsareusuallydefectivewhenoneoftheallelicproductsisnonfunctional enzymesusuallyrequirebothallelicproductstobenonfunctionaltoproduceamutantphenotype 26 27 28 3 Autosomalrecessiveinheritance therecessiveaffectedindividualtheheterozygouscarrierindividualthehomozygousnormalindividual dd Dd DD 29 affectedindividualshaveparentswithnormalphenotypes Thefirst andmostimportant 30 Supposethediseaseaffectsoneintenthousandlivebirthstheheterozygotefrequencyinthepopulationoneinfifty seepopulationgeneticsforcalculations 31 ThePunnettSquareforautosomalrecessivediseaseswithanaffectedchildinthefamilyalmostalwayslookslikethefollowing 32 WherethefatherandmotherarebothDd ThePunnetSquareshowstheoriginofthefamousMendelianrationof3 4normalto1 4affected 33 Formostautosomalrecessivediseases butnotall theheterozygotecannotbedistinguishedfromthenormalhomozygote InthenormalphenotypecategoriesofoffspringintheabovePunnettSquare DdandDDproducethesamenormalphenotype pleasenotethattwoofthethreeareheterozygotes carriers oneofthethreeishomozygousnormal 34 Withinthenormalsiblingsofanaffectedindividualtheprobabilityofbeingacarrieris2 3 35 36 37 Therearefivehallmarksofautosomalrecessiveinheritance 1 Malesandfemalesareequallylikelytobeaffected 2 Onaverage therecurrencerisktotheunbornsiblingofanaffectedindividualis1 4 3 Thetraitischaracteristicallyfoundinsiblings notparentsofaffectedortheoffspringofaffected 4 Parentsofaffectedchildrenmayberelated Therarerthetraitinthegeneralpopulation themorelikelyaconsanguineousmatingisinvolved 5 Thetraitmayappearasanisolated sporadic eventinsmallsibships 38 Samplepedigree 39 Whenconsanguinityisinvolved i e matingsbetweenrelatedindividuals intheproductionofanaffectedchildtheassignmentofprobabilitieschanges especiallyintherarerautosomalrecessivediseases 40 Samplepedigree 41 为什么近亲婚配时子女发病风险明显增高 在3 4代之内有共同祖先的个体之间的婚配称为近亲婚配 有共同祖先的两个个体 在某一基因座上带有相同基因 由共同祖先传递来 的概率用亲缘系数 coefficientofrelationship 衡量 42 44 依据亲缘系数的大小 分成不同的亲属级别 45 家族无患者时 近亲婚配发病风险增高 某种AR 致病基因频率为1 100 1 1000携带者频率为1 50 1 500 2pq 随机婚配1 50X1 50X1 4 1 10000近亲婚配1 50X1 8X1 4 1 16001 500X1 500X1 4 1 10000001 500X1 8X1 4 1 16000 群体中AR遗传病的携带者频率越低 近亲婚配后代的相对发病风险就越高 46 家族有患者时 近亲婚配时子女发病风险明显增高 设某种AR遗传病的发病率为1 10000 近亲婚配时 1 3 1 3 1 4 随机婚配时 1 3 1 50 1 4 47 1的发病风险为 2 3 1 4 1 4 48 例如 婴儿黑朦性痴呆 患者眼底病变 49 例如 肝豆状核变性 50 苯丙酮尿症 PKU 遗传方式 AR 关键酶 苯丙氨酸羟化酶 PAH 基因定位 12q22 24 PAH基因全长85kb 含13个外显子 基因缺陷以点突变为主 临床表现 苯丙酮酸 苯乳酸 苯乙酸 毛发 皮肤和尿有特殊气味患者毛发和皮肤颜色浅 51 苯丙氨酸酪氨酸多巴儿茶酚胺 苯丙酮酸 苯乙酸苯乳酸 尿黑酸 乙酰乙酸 黑色素 甲状腺素 苯丙氨酸 酪氨酸代谢 52 白化病 遗传方式 AR 关键酶 酪氨酸酶 基因定位 11q14 21 基因全长50kb 含5个外显子 基因缺陷以点突变为主 临床表现 皮肤 毛发淡黄色或银白虹膜及瞳孔呈淡红色 羞明 眼球震颤易患皮肤癌 53 白化病 54 白化病典型家系 55 56 4 X linkeddominantinheritance WhenanX linkedgeneissaidtoexpressdominantinheritance itmeansthatasingledoseofthemutantallelewillaffectthephenotypeofthefemale ArecessiveX linkedgenerequirestwodosesofthemutantalleletoaffectthefemalephenotype 57 Affectedfatherxnormalmother Affectedmotherxnormalfather hemizygote Criss crossinheritance 58 ThefollowingarethehallmarksofX linkeddominantinheritance 1 Thetraitisneverpassedfromfathertoson 2 Alldaughtersofanaffectedmaleandanormalfemaleareaffected Allsonsofanaffectedmaleandanormalfemalearenormal 3 Matingsofaffectedfemalesandnormalmalesproduce1 2thesonsaffectedand1 2thedaughtersaffected 4 Malesareusuallymoreseverelyaffectedthanfemales Thetraitmaybelethalinmales 5 Inthegeneralpopulation femalesaremorelikelytobeaffectedthanmales evenifthediseaseisnotlethalinmales 59 Samplepedigree 60 Incontinentiapigmenti 61 VitaminD resistantRickets 62 63 5 X linkedrecessiveinheritance EveryonehasheardofsomeX linkedrecessivediseaseeventhoughtheyare ingeneral rare Hemophilia Duchennemusculardystrophy Beckermusculardystrophy andLesch Nyhansyndromearerelativelyrareinmostpopulations butbecauseofadvancesinmoleculargeneticstheyreceiveattentioninthemedia 64 65 66 ThehallmarksofX linkedrecessiveinheritance 1 AswithanyX linkedtrait thediseaseisneverpassedfromfathertoson 2 Malesaremuchmorelikelytobeaffectedthanfemales 3 Allaffectedmalesinafamilyarerelatedthroughtheirmothers 4 Traitordiseaseistypicallypassedfromanaffectedgrandfather throughhiscarrierdaughters tohalfofhisgrandsons 67 Samplepedigree 68 Hemophilia 69 70 71 DMD 72 6 Y linked AgeneontheYchromosome AY linkedgeneisbynecessitypassedfromfathertoson sincetheYchromosomecanonlybetransmittedbyamantohismaleprogeny 73 AnumberofgeneswereknowntobeY linkedincluding ASMTY acetylserotoninmethyltransferase TSPY testis specificprotein IL3RAY interleukin 3receptor SRY sex determiningregion TDF testisdeterminingfactor ZFY zincfingerprotein PRKY protei