疾病的單基因遺傳

1、03 疾病的單基因遺傳Monogenic Inheritance,,single-gene disorder or monogenic disorder Some disorders result when a mutation causes the product of a single gene to be altered or missing. These disorders are in

2、herited in simple patterns similar to or identical with those described by Mendel for certain discrete characteristics in garden peas. Therefore, it’s also called Mendelian diseases.,3,☆ 病例分析,姓名：不幸××男性，69歲，已3

3、次經(jīng)中南大學(xué)湘雅二醫(yī)院臨床確診異時(shí)性結(jié)直腸癌，即52歲時(shí)診斷為右半結(jié)腸癌，61歲發(fā)生乙狀結(jié)腸癌，68歲患直腸癌。,家族史：先證者的兒子于25歲和37歲兩次診斷為異時(shí)性結(jié)直腸癌。其家族4代31人中有17人共21例次診斷結(jié)直腸癌等惡性腫瘤，其中12名(70.6 %)患者患有結(jié)直腸癌, 另6名患者發(fā)現(xiàn)結(jié)直腸外惡性腫瘤,包括子宮內(nèi)膜、胃、腦、肝臟等。 所有患者惡性腫瘤的平均發(fā)病年齡是41歲, 結(jié)直腸癌的平均發(fā)病年齡是42.9歲, 患者的男女性別

4、比例是10∶7。,1. Pedigree and Proband,Humans are unique among organisms in many ways, but one way which is near and dear to a geneticist's heart is that humans are not susceptible to genetic experimentation.,,The study of

5、 inherited Mendelian traits in humans must rely on observations made while working with individual families.,,Classical cross fertilization breeding experiments as performed by Mendel are not allowed in humans! Human gen

6、eticists are not allowed to selectively breed for the traits they wish to study!,,One of most powerful tools in human genetic studies is pedigree analysis.,,pedigree They are graphic representations of a f

7、amily 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 i

8、nherited.,,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.,Symbols,,12,,調(diào)查資料繪制系譜,家族史：先證

9、者的兒子于25歲和37歲兩次診斷為異時(shí)性結(jié)直腸癌。其家族4代31人中有17人共21例次診斷結(jié)直腸癌等惡性腫瘤，其中12名(70.6 %)患者患有結(jié)直腸癌, 另6名患者發(fā)現(xiàn)結(jié)直腸外惡性腫瘤,包括子宮內(nèi)膜、胃、腦、肝臟等。 所有患者惡性腫瘤的平均發(fā)病年齡是41歲, 結(jié)直腸癌的平均發(fā)病年齡是42.9歲, 患者的男女性別比例是10∶7。,,?,14,判斷遺傳性非息肉性結(jié)直腸癌的阿姆斯特丹I標(biāo)準(zhǔn)：家族中至少有3例組織病理學(xué)證實(shí)的結(jié)直腸癌患者，其

10、中1例是另外2例的一級(jí)親屬；至少有連續(xù)兩代人發(fā)生結(jié)直腸癌；至少有1例患者是在50歲之前發(fā)??；排除家族性腺瘤性息肉病。,結(jié)直腸癌是一種最常見(jiàn)的內(nèi)臟惡性腫瘤,發(fā)病率較高，其中大約有15％～20％為家族性發(fā)病, 如家族性腺瘤息肉（Familial adenomatous polyposis, FAP）和遺傳性非息肉性結(jié)直腸癌（Hereditary nonpolyposis colorectal cancer, HNPCC）。,,尋找致病

11、基因及致病突變,遺傳性非息肉性結(jié)直腸癌(HNPCC)的發(fā)生與DNA錯(cuò)配修復(fù)缺陷有關(guān)，已知至少有5種錯(cuò)配修復(fù)（mismatch repair，MMR）基因(MSH2、MLH1、MSH6、PMS1 和PMS2 )與其有關(guān)。目前已在HNPCC患者中發(fā)現(xiàn)了400多種MMR 基因的突變，其中 MSH2 基因突變約占50％，MLH1 基因突變約占39％。,15,MSH2 和MLH1 基因篩查,,通過(guò)PCR擴(kuò)增和序列測(cè)定, 在先證者 gDNA

12、中發(fā)現(xiàn)了MSH2 基因7號(hào)外顯子中的一種國(guó)內(nèi)外尚未見(jiàn)報(bào)道的新突變,該突變由于4個(gè)核苷酸（CCGA）的插入導(dǎo)致該4個(gè)核苷酸重復(fù) (MSH2: c.1215_1218dupCCGA)，形成移碼突變，產(chǎn)生異常截短蛋白。所有被檢測(cè)的患者均發(fā)現(xiàn)該突變，表型正常的成年家系成員均正常。另外，50個(gè)家系外正常對(duì)照中未發(fā)現(xiàn)該基因突變。我們確認(rèn)該突變導(dǎo)致了該家系的遺傳性非息肉性結(jié)直腸癌的發(fā)生。,16,17,,癥狀前診斷,家系中1人（IV-1）為突變基因攜帶

13、者。該攜帶者（IV-1）年僅16歲，由于年齡尚小，尚未到發(fā)病年齡，目前未檢出結(jié)直腸癌或其他癌癥，但應(yīng)引起高度重視。,MSH2 mutation,遺傳性非息肉性結(jié)直腸癌,Autosomal dominant inheritance,2. Autosomal dominant inheritance,The pattern of autosomal dominant inheritance is perhaps the easiest ty

14、pe 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.,,There are three reasons why an individual with an auto

15、somal dominant disease should always be considered as being a heterozygote until proven otherwise.,homozygotes？,heterozygotes？,,Suppose a father is heterozygous for an autosomal dominant gene, with allele D, the mutant d

16、ominant 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:,,O

17、ne 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.,,Sample Pedigree,?,,With the understanding that almost all af

18、fected 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.,

19、There are four hallmarks of autosomal dominant inheritance: (1) Except for new mutations, which are rare in nature and extremely rare on examination pedigrees, and the complexities of incomplete penetrance to be di

20、scussed later, every affected individual has an affected biological parent. There is no skipping of generations. (2) Males and females have an equally likely chance of inheriting the mutant allele and being affecte

21、d. The recurrence risk of each child of an affected parent is 1/2.,,(3) Normal siblings of affected individuals do not transmit the trait to their offspring. (4)The defective product of the gene is usually a struct

22、ural protein, not an enzyme. 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.,,

23、,,?,3. Autosomal recessive inheritance,the recessive affected individual the heterozygous carrier individualthe homozygous normal individual,,dd,Dd,DD,,,affected individuals have parents with normal phenotypes.,The fir

24、st, and most important,,Suppose the disease affects one in ten thousand live births the heterozygote frequency in the population one in fifty (see population genetics for calculations).,,The Punnett Square for autoso

25、mal recessive diseases with an affected child in the family almost always looks like the following:,,Where the father and mother are both Dd. The Punnet Square shows the origin of the famous Mendelian ration of 3/4 norma

26、l to 1/4 affected.,,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

27、 and DD produce the same normal phenotype), please note that two of the three are heterozygotes (carriers); one of the three is homozygous normal.,,Within the normal siblings of an affected individual the probability of

28、being a carrier is 2/3.,There are five hallmarks of autosomal recessive inheritance: (1) Males and females are equally likely to be affected.(2) On average, the recurrence risk to the unborn sibling of an affected in

29、dividual 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 populati

30、on, the more likely a consanguineous mating is involved.(5) The trait may appear as an isolated (sporadic) event in small sibships.,,Sample pedigree,?,,When consanguinity is involved, i.e., matings between related indi

31、viduals, in the production of an affected child the assignment of probabilities changes, especially in the rarer autosomal recessive diseases.,,Sample pedigree,? 為什么近親婚配時(shí)子女發(fā)病風(fēng)險(xiǎn)明顯增高？,在3～4代之內(nèi)有共同祖先的個(gè)體之間的婚配稱(chēng)為近親婚配。,有共同祖先的兩個(gè)個(gè)體

32、，在某一基因座上帶有相同基因（由共同祖先傳遞來(lái)）的概率用親緣系數(shù)(coefficient of relationship)衡量。,§ 依據(jù)親緣系數(shù)的大小，分成不同的親屬級(jí)別,家族無(wú)患者時(shí)，近親婚配發(fā)病風(fēng)險(xiǎn)增高,某種AR，致病基因頻率為1/100～1/1000 攜帶者頻率為1/50～1/500（2pq）隨機(jī)婚配 1/50 X 1/50 X 1/4=1/10000近親婚配 1/50 X 1/8 X 1/

33、4= 1/1600 1/500 X 1/500 X 1/4=1/1 000 000 1/500 X 1/8 X 1/4= 1/16000,群體中AR遺傳病的攜帶者頻率越低，近親婚配后代的相對(duì)發(fā)病風(fēng)險(xiǎn)就越高。,家族有患者時(shí)，近親婚配時(shí)子女發(fā)病風(fēng)險(xiǎn)明顯增高,設(shè)某種AR遺傳病的發(fā)病率為1/10000,近親婚配時(shí)： 1/3×1/3×1/4,隨機(jī)婚配時(shí)： 1/3

34、×1/50×1/4,Ⅳ1的發(fā)病風(fēng)險(xiǎn)為：2/3 ×1/4×1/4,例如：嬰兒黑朦性癡呆,患者眼底病變,例如：肝豆?fàn)詈俗冃?苯丙酮尿癥（PKU）,? 遺傳方式：AR? 關(guān) 鍵 酶：苯丙氨酸羥化酶（PAH）? 基因定位：12q22-24? PAH基因全長(zhǎng)85kb，含13個(gè)外顯子? 基因缺陷以點(diǎn)突變?yōu)橹? 臨床表現(xiàn)： 苯丙酮酸↑苯乳酸↑苯乙酸↑ 毛發(fā)、皮膚和尿有特殊氣味

35、 患者毛發(fā)和皮膚顏色淺,苯丙氨酸 酪氨酸 多巴 兒茶酚胺,,,,苯丙酮酸,,苯乙酸 苯乳酸,,,,尿黑酸,,乙酰乙酸,,黑色素,,甲狀腺素,苯丙氨酸、酪氨酸代謝,,白 化 病,? 遺傳方式：AR? 關(guān) 鍵 酶：酪氨酸酶? 基因定位：11q14-21? 基因全長(zhǎng)50kb，含5個(gè)外顯子? 基因缺陷以點(diǎn)突變?yōu)橹? 臨床表現(xiàn)：

36、 皮膚、毛發(fā)淡黃色或銀白 虹膜及瞳孔呈淡紅色，羞明，眼球震顫 易患皮膚癌,,白 化 病,白化病典型家系,,4. 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

37、 affect the phenotype of the female. A recessive X-linked gene requires two doses of the mutant allele to affect the female phenotype.,Affected father x normal mother. Affected mother x normal father.,hemizygote

38、,Criss-cross inheritance,The following are the hallmarks of X-linked dominant inheritance: (1)The trait is never passed from father to son.(2)All daughters of an affected male and a normal female are affected. All so

39、ns 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 fema

40、les. 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.,,Sample pedigree,?,,Incontinentia pigmenti,,Vitami

41、n D-resistant Rickets,,,,5. 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,

42、 and Lesch-Nyhan syndrome are relatively rare in most populations, but because of advances in molecular genetics they receive attention in the media.,,The hallmarks of X-linked recessive inheritance(1) As with any X-li

43、nked 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 ty

44、pically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.,,Sample pedigree,?,,Hemophilia,,DMD,,6. Y-linked,A gene on the Y chromosome. A Y-linked gene is by necessity passed fr

45、om father to son, since the Y chromosome can only be transmitted by a man to his male progeny.,,A number of genes were known to be Y-linked including: ASMTY (acetylserotonin methyltransferase), TSPY (testis-s

46、pecific 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-macroph

47、age 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 fac

48、tor 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).,,Sample pedigree,

49、?,,,Basic Pattern of Single Gene Inheritance Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive Y-linked,教學(xué)要求,掌握單基因疾病的遺傳方式 掌握各種單基因疾病遺傳方式的特征 熟悉系譜與系譜分析法

50、 了解常見(jiàn)的幾種單基因遺傳疾病,,思考練習(xí)題正常男性A(不是致病基因攜帶者)與表型正常女性B婚配,生一男孩C(表型正常)。另一對(duì)夫(D)婦(E)(表型均正常),婚后生育二女(F和G)一兒（H）。 G是苯丙酮尿癥患者， F、H正常。F與C婚后生育一苯丙酮尿癥男孩I和一甲型血友病男孩J。H與其姨表妹K婚配，生一女L。已知苯丙酮尿癥的發(fā)病率為1/3600。要求：1）根據(jù)題意繪制系譜；2）回答下列問(wèn)題：①寫(xiě)出B的基因型（設(shè)苯丙酮尿癥致病