疾病的单基因遗传课件

03 疾病的单基因遗传Monogenic Inheritance2021/3/121single-gene disorder or monogenic disorder Somedisordersresultwhenamutationcausestheproductofasinglegenetobealteredormissing.These disorders are inherited in simple patterns similar to or identical with those described by Mendel for certain discrete characteristics in garden peas.Therefore,its also called Mendelian diseases.2021/3/1223 病例分析病例分析姓名：不幸姓名：不幸男性，男性，6969岁，已岁，已3 3次经中南大学湘雅二医院临床确诊异时性次经中南大学湘雅二医院临床确诊异时性结直肠癌，即结直肠癌，即5252岁时诊断为右半结肠癌，岁时诊断为右半结肠癌，6161岁发生乙状结肠岁发生乙状结肠癌，癌，6868岁患直肠癌。岁患直肠癌。家族史：家族史：先证者先证者的儿子于的儿子于2525岁和岁和3737岁两次诊断为异时性结直岁两次诊断为异时性结直肠癌。其家族肠癌。其家族4 4代代3131人中有人中有1717人共人共2121例次诊断结直肠癌等恶例次诊断结直肠癌等恶性肿瘤，其中性肿瘤，其中1212名名(70.6%)(70.6%)患者患有结直肠癌患者患有结直肠癌,另另6 6名患者名患者发现结直肠外恶性肿瘤发现结直肠外恶性肿瘤,包括子宫内膜、胃、脑、肝脏等。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所有患者恶性肿瘤的平均发病年龄是4141岁岁,结直肠癌的平均结直肠癌的平均发病年龄是发病年龄是42.942.9岁岁,患者的男女性别比例是患者的男女性别比例是10107 7。2021/3/1231.Pedigree and Proband Humans are unique among organisms in many ways,but one way which is near and dear to a geneticists heart is that humans are not susceptible to genetic experimentation.2021/3/124 The study of inherited Mendelian traits in humans must rely on observations made while working with individual families.2021/3/125 Classical cross fertilization breeding experiments as performed by Mendel are not allowed in humans!Human geneticists are not allowed to selectively breed for the traits they wish to study!2021/3/126 One of most powerful tools in human genetic studies is pedigree analysis.2021/3/127pedigree They are graphic representations of a family tree which show the biological relationship of the index case,or proband or propositus to the rest of the individuals.A family tree diagram that shows how a particular genetic trait or disease has been inherited.2021/3/128 When human geneticists first began to publish family studies,they used a variety of symbols and conventions.Now there are agreed upon standards for the construction of pedigrees.2021/3/129Symbols2021/3/12102021/3/121112调查资料调查资料绘制系谱绘制系谱 家族史：家族史：先证者先证者的儿子于的儿子于2525岁和岁和3737岁两次诊断为异时性结直肠癌。其家族岁两次诊断为异时性结直肠癌。其家族4 4代代3131人中有人中有1717人共人共2121例次诊断结直肠癌等恶性肿瘤，其中例次诊断结直肠癌等恶性肿瘤，其中1212名名(70.6%)(70.6%)患者患有结直患者患有结直肠癌肠癌,另另6 6名患者发现结直肠外恶性肿瘤名患者发现结直肠外恶性肿瘤,包括子宫内膜、胃、脑、肝脏等。包括子宫内膜、胃、脑、肝脏等。所所有患者恶性肿瘤的平均发病年龄是有患者恶性肿瘤的平均发病年龄是4141岁岁,结直肠癌的平均发病年龄是结直肠癌的平均发病年龄是42.942.9岁岁,患患者的男女性别比例是者的男女性别比例是10107 7。2021/3/1212?2021/3/121314判断遗传性非息肉性结直肠判断遗传性非息肉性结直肠癌的阿姆斯特丹癌的阿姆斯特丹I I标准：标准：1.1.家族中至少有家族中至少有3 3例组织病例组织病理学证实的结直肠癌患理学证实的结直肠癌患者，其中者，其中1 1例是另外例是另外2 2例例的一级亲属；的一级亲属；2.2.至少有连续两代人发生至少有连续两代人发生结直肠癌；结直肠癌；3.3.至少有至少有1 1例患者是在例患者是在5050岁岁之前发病；之前发病；4.4.排除家族性腺瘤性息肉排除家族性腺瘤性息肉病。病。结直肠癌结直肠癌是一种最常见的内脏恶性肿瘤是一种最常见的内脏恶性肿瘤,发病率较高，其中大约有发病率较高，其中大约有15152020为家为家族性发病族性发病,如家族性腺瘤息肉（如家族性腺瘤息肉（Familial Familial adenomatous polyposis,FAPadenomatous polyposis,FAP）和遗传性）和遗传性非息肉性结直肠癌（非息肉性结直肠癌（Hereditary Hereditary nonpolyposis colorectal cancer,nonpolyposis colorectal cancer,HNPCCHNPCC）。）。寻找致病基因寻找致病基因与致病突变与致病突变2021/3/1214 遗遗传传性性非非息息肉肉性性结结直直肠肠癌癌(HNPCC)(HNPCC)的的发发生生与与DNADNA错错配配修修复复缺缺陷陷有有关关，已已知知至至少少有有5 5种种错错配配修修复复（mismatch mismatch repairrepair，MMRMMR）基基因因(MSH2MSH2、MLH1MLH1、MSH6MSH6、PMS1PMS1 和和PMS2PMS2 )与与其其有有关关。目目前前已已在在HNPCCHNPCC患患者者中中发发现现了了400400多多种种MMR MMR 基基因因的的突突变变，其其中中 MSH2 MSH2 基基因因突突变变约约占占5050，MLH1 MLH1 基基因突变约占因突变约占3939。15MSH2 MSH2 和和MLH1MLH1 基因筛查基因筛查2021/3/1215通过通过PCRPCR扩增和序列测定扩增和序列测定,在先在先证者证者 gDNA gDNA 中发现了中发现了MSH2MSH2 基因基因7 7号外显子号外显子中的一种国内外尚未中的一种国内外尚未见报道的新突变见报道的新突变,该突变由于该突变由于4 4个核苷酸（个核苷酸（CCGACCGA）的插入导致）的插入导致该该4 4个核苷酸重复个核苷酸重复 (MSH2MSH2:c.1215_1218dupCCGA)c.1215_1218dupCCGA)，形成移，形成移码突变，产生异常截短蛋白。码突变，产生异常截短蛋白。所有被检测的患者均发现该突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变，表型正常的成年家系成员均正常。另外，均正常。另外，5050个家系外正个家系外正常对照中未发现该基因突变。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的遗传性非息肉性结直肠癌的发生。发生。162021/3/121617症状前诊断症状前诊断家系中家系中1 1人（人（IV-1IV-1）为突变基）为突变基因携带者。该携带者（因携带者。该携带者（IV-IV-1 1）年仅）年仅1616岁，由于年龄尚小岁，由于年龄尚小，尚未到发病年龄，目前未，尚未到发病年龄，目前未检出结直肠癌或其他癌症，检出结直肠癌或其他癌症，但应引起高度重视。但应引起高度重视。2021/3/1217MSH2 mutation遗传性非息肉性结直肠癌遗传性非息肉性结直肠癌Autosomal dominant inheritanceAutosomal dominant inheritance2021/3/12182.Autosomal dominant inheritance The pattern of autosomal dominant inheritance is perhaps the easiest type of Mendelian inheritance to recognize in a pedigree.One dose of the mutant gene,one mutant allele,is all that is required for the expression of the phenotype.2021/3/1219 There are three reasons why an individual with an autosomal dominant disease should always be considered as being a heterozygote until proven otherwise.homozygotes？heterozygotes？2021/3/1220 Suppose a father is heterozygous for an autosomal dominant gene,with allele D,the mutant dominant allele,and allele d,the recessive normal allele.He can produce two types of gametes,D and d.Suppose also his wife is homozygous normal,having both d alleles.The Punnett Square is constructed as follows:2021/3/1221 One gamete comes from each parent to produce the genotype of the offspring.Two out of the four possible combinations are affected;two out of four are normal.2021/3/1222SamplePedigree?2021/3/1223 With the understanding that almost all affected individuals are heterozygotes,and that in most matings involving a person with an autosomal dominant trait the other partner will be homozygous normal,there are four hallmarks of autosomal dominant inheritance.2021/3/1224Therearefourhallmarksofautosomaldominantinheritance:(1)Except for new mutations,which are rare in nature and extremely rare on examination pedigrees,and the complexities of incomplete penetrance to be discussed later,everyaffectedindividualhasanaffectedbiologicalparent.Thereisnoskippingofgenerations.(2)Males and females have an equally likely chance of inheriting the mutant allele and being affected.Therecurrenceriskofeachchildofanaffectedparentis1/2.2021/3/1225 (3)Normalsiblingsofaffectedindividualsdonottransmitthetraittotheiroffspring.(4)Thedefectiveproductofthegeneisusuallyastructuralprotein,notanenzyme.Structural proteins are usually defective when one of the allelic products is nonfunctional;enzymes usually require both allelic products to be nonfunctional to produce a mutant phenotype.2021/3/12262021/3/1227?2021/3/1228DDDdthe recessive affected individual the heterozygous carrier individualthe homozygous normal individualdd2021/3/1229 affected individuals have parents with normal phenotypes.The first,and most important2021/3/1230 Suppose the disease affects one in ten thousand live births the heterozygote frequency in the population one in fifty(see population genetics for calculations).2021/3/1231 The Punnett Square for autosomal recessive diseases with an affected child in the family almost always looks like the following:2021/3/1232 Where the father and mother are both Dd.The Punnet Square shows the origin of the famous Mendelian ration of 3/4 normal to 1/4 affected.2021/3/1233 For most autosomal recessive diseases,but not all,the heterozygote cannot be distinguished from the normal homozygote.In the normal phenotype categories of offspring in the above Punnett Square(Dd and DD produce the same normal phenotype),please note that two of the three are heterozygotes(carriers);one of the three is homozygous normal.2021/3/1234 Within the normal siblings of an affected individual the probability of being a carrier is 2/3.2021/3/12352021/3/12362021/3/1237Therearefivehallmarksofautosomalrecessiveinheritance:(1)Males and females are equally likely to be affected.(2)On average,the recurrence risk to the unborn sibling of an affected individual is 1/4.(3)The trait is characteristically found in siblings,not parents of affected or the offspring of affected.(4)Parents of affected children may be related.The rarer the trait in the general population,the more likely a consanguineous mating is involved.(5)The trait may appear as an isolated(sporadic)event in small sibships.2021/3/1238Samplepedigree?2021/3/1239 When consanguinity is involved,i.e.,matings between related individuals,in the production of an affected child the assignment of probabilities changes,especially in the rarer autosomal recessive diseases.2021/3/1240Samplepedigree2021/3/1241 为什么近亲婚配时子女发病风险明显增高？为什么近亲婚配时子女发病风险明显增高？在在3 34 4代之内有共同祖先的个体之间的代之内有共同祖先的个体之间的婚配称为婚配称为近亲婚配近亲婚配。有共同祖先的两个个体，在某一基因座上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）的概率用带有相同基因（由共同祖先传递来）的概率用亲缘系数亲缘系数亲缘系数亲缘系数(coefficient of relationship)(coefficient of relationship)衡量。衡量。2021/3/12422021/3/1243 依据亲缘系数的大小，分成不同的亲属级别依据亲缘系数的大小，分成不同的亲属级别亲属级别亲属级别亲缘系数亲缘系数一级亲属一级亲属(亲子、同胞亲子、同胞)1/21/2二级亲属（祖父母等）二级亲属（祖父母等）1/41/4三级亲属（表兄妹等）三级亲属（表兄妹等）1/81/82021/3/1244家族无患者时，近亲婚配发病风险增高家族无患者时，近亲婚配发病风险增高某种某种ARAR，致病基因频率为，致病基因频率为1/1001/1001/10001/1000 携带者频率为携带者频率为1/501/501/5001/500（2pq2pq）随机婚配随机婚配 1/50 X 1/50 X 1/4=1/100001/50 X 1/50 X 1/4=1/10000近亲婚配近亲婚配 1/50 X 1/8 X 1/4=1/16001/50 X 1/8 X 1/4=1/1600 1/500 X 1/500 X 1/4=1/1 000 000 1/500 X 1/500 X 1/4=1/1 000 000 1/500 X 1/8 X 1/4=1/16000 1/500 X 1/8 X 1/4=1/16000 群体中群体中ARAR遗传病的携带者频率越低，近亲婚配后代的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。相对发病风险就越高。2021/3/1245 家族有患者时，近亲婚配时子女发病风险明显家族有患者时，近亲婚配时子女发病风险明显增高增高设某种设某种ARAR遗传病的发病率遗传病的发病率为为1/100001/10000近亲婚配时：近亲婚配时：1/31/31/41/31/31/4随机婚配时：随机婚配时：1/31/501/41/31/501/42021/3/12461 21 2 3 4 51 2 31 1的发病风险为：的发病风险为：2/3 1/41/42021/3/1247例如：婴儿黑朦性痴呆例如：婴儿黑朦性痴呆 患患者者眼眼底底病病变变2021/3/1248例如：肝豆状核变性例如：肝豆状核变性2021/3/1249苯丙酮尿症（苯丙酮尿症（PKU）遗传方式：遗传方式：ARAR 关关 键键 酶：苯丙氨酸羟化酶（酶：苯丙氨酸羟化酶（PAHPAH）基因定位：基因定位：12q22-2412q22-24 PAHPAH基因全长基因全长85kb85kb，含，含1313个外显子个外显子 基因缺陷以点突变为主基因缺陷以点突变为主 临床表现：临床表现：苯丙酮酸苯丙酮酸苯乳酸苯乳酸苯乙酸苯乙酸 毛发、皮肤和尿有特殊气味毛发、皮肤和尿有特殊气味 患者毛发和皮肤颜色浅患者毛发和皮肤颜色浅2021/3/1250苯丙氨酸苯丙氨酸 酪氨酸酪氨酸 多巴多巴 儿茶酚胺儿茶酚胺苯丙酮酸苯丙酮酸苯乙酸苯乙酸 苯乳酸苯乳酸尿黑酸尿黑酸乙酰乙酸乙酰乙酸黑色素黑色素甲状腺素甲状腺素苯丙氨酸、酪氨酸代谢苯丙氨酸、酪氨酸代谢2021/3/1251白白 化化 病病 遗传方式：遗传方式：ARAR 关关 键键 酶：酪氨酸酶酶：酪氨酸酶 基因定位：基因定位：11q14-2111q14-21 基因全长基因全长50kb50kb，含，含5 5个外显子个外显子 基因缺陷以点突变为主基因缺陷以点突变为主 临床表现：临床表现：皮肤、毛发淡黄色或银白皮肤、毛发淡黄色或银白 虹膜与瞳孔呈淡红色，羞明，眼球震颤虹膜与瞳孔呈淡红色，羞明，眼球震颤 易患皮肤癌易患皮肤癌2021/3/1252白白 化化 病病2021/3/1253白化病典型家系白化病典型家系2021/3/12542021/3/12554.X-linked dominant inheritance When an X-linked gene is said to express dominant inheritance,it means that a single dose of the mutant allele will affect the phenotype of the female.A recessive X-linked gene requires two doses of the mutant allele to affect the female phenotype.2021/3/1256Affected father x normal mother.Affected mother x normal father.hemizygoteCriss-cross inheritance2021/3/1257ThefollowingarethehallmarksofX-linkeddominantinheritance:(1)The trait is never passed from father to son.(2)All daughters of an affected male and a normal female are affected.All sons of an affected male and a normal female are normal.(3)Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected.(4)Males are usually more severely affected than females.The trait may be lethal in males.(5)In the general population,females are more likely to be affected than males,even if the disease is not lethal in males.2021/3/1258Samplepedigree?2021/3/1259Incontinentiapigmenti2021/3/1260VitaminD-resistantRickets2021/3/12612021/3/12625.X-linked recessive inheritance Everyone has heard of some X-linked recessive disease even though they are,in general,rare.Hemophilia,Duchenne muscular dystrophy,Becker muscular dystrophy,and Lesch-Nyhan syndrome are relatively rare in most populations,but because of advances in molecular genetics they receive attention in the media.2021/3/12632021/3/12642021/3/1265ThehallmarksofX-linkedrecessiveinheritance(1)As with any X-linked trait,the disease is never passed from father to son.(2)Males are much more likely to be affected than females.(3)All affected males in a family are related through their mothers.(4)Trait or disease is typically passed from an affected grandfather,through his carrier daughters,to half of his grandsons.2021/3/1266Samplepedigree?2021/3/1267Hemophilia2021/3/12682021/3/12692021/3/1270DMD2021/3/12716.Y-linked A gene on the Y chromosome.A Y-linked gene is by necessity passed from father to son,since the Y chromosome can only be transmitted by a man to his male progeny.2021/3/1272AnumberofgeneswereknowntobeY-linkedincluding:ASMTY(acetylserotonin methyltransferase),TSPY(testis-specific protein),IL3RAY(interleukin-3 receptor),SRY(sex-determining region),TDF(testis determining factor),ZFY(zinc finger protein),PRKY(protein kinase,Y-linked),AMGL(amelogenin),CSF2RY(granulocyte-macrophage colony-stimulating factor receptor,alpha subunit on the Y chromosome),ANT3Y(adenine nucleotide translocator-3 on the Y),AZF2(azoospermia factor 2),BPY2(basic protein on the Y chromosome),AZF1(azoospermia factor 1),DAZ(deleted in azoospermia),RBM1(RNA binding motif protein,Y chromosome,family 1,member A1),RBM2(RNA binding motif protein 2)and UTY(ubiquitously transcribed TPR gene on Y chromosome).2021/3/1273Samplepedigree?2021/3/12742021/3/1275Basic Pattern of Single Gene Inheritance Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive Y-linked2021/3/1276教学要求教学要求1.掌握单基因疾病的遗传方式掌握单基因疾病的遗传方式2.掌握各种单基因疾病遗传方式的特征掌握各种单基因疾病遗传方式的特征3.熟悉系谱与系谱分析法熟悉系谱与系谱分析法4.了解常见的几种单基因遗传疾病了解常见的几种单基因遗传疾病2021/3/1277思考练习题思考练习题正常男性正常男性A(不是致病基因携带者不是致病基因携带者)与表型正常女性与表型正常女性B婚配婚配,生一男生一男孩孩C(表型正常表型正常)。另一对夫。另一对夫(D)妇妇(E)(表型均正常表型均正常),婚后生育二女婚后生育二女(F和和G)一儿（一儿（H）。）。G是苯丙酮尿症患者，是苯丙酮尿症患者，F、H正常。正常。F与与C婚后生育一苯丙酮尿症男孩婚后生育一苯丙酮尿症男孩I和一甲型血友病男孩和一甲型血友病男孩J。H与其姨表与其姨表妹妹K婚配，生一女婚配，生一女L。已知苯丙酮尿症的发病率为。已知苯丙酮尿症的发病率为1/3600。要求：要求：1）根据题意绘制系谱；）根据题意绘制系谱；2）回答下列问题：）回答下列问题：写出写出B的基因型（设苯丙酮尿症致病基因基因为的基因型（设苯丙酮尿症致病基因基因为d，甲型血友，甲型血友病致病基因为病致病基因为h）写出写出C的基因型，的基因型，写出写出F的基因型，的基因型，H是苯丙酮尿症致是苯丙酮尿症致病基因基因携带者的几率是多少？病基因基因携带者的几率是多少？G是甲型血友病致病基因是甲型血友病致病基因携带者的几率是多少？携带者的几率是多少？、L苯丙酮尿发病几率？苯丙酮尿发病几率？2021/3/1278分析下列系谱图的遗传方式、判断依据、先证者与分析下列系谱图的遗传方式、判断依据、先证者与分析下列系谱图的遗传方式、判断依据、先证者与分析下列系谱图的遗传方式、判断依据、先证者与其父母的基因型。其父母的基因型。其父母的基因型。其父母的基因型。2021/3/12792021/3/12802021/3/12812021/3/12822021/3/1283Thank you!Thank you!2021/3/1284