醫(yī)學(xué)遺傳學(xué)課件：chapter 6 Single gene disorder

1、Chapter 6 Single-gene Disorder A Gene A Disease Or Monogenic Disorder 1 醫(yī)學(xué)遺傳學(xué) Chapter 6 ? Homozygote AA or aa Heterozygote Aa Genotype & Phenotype Dominant A Recessive a Allele - - A/a 2 醫(yī)學(xué)遺傳學(xué) Chapter 6 ? The diseases that are the result of a single mutant gene that has a large effect on phenotype a

2、nd that are inherited in simple patterns similar to or identical with those described by Mendel for certain discrete characteristics in garden peas. 3 醫(yī)學(xué)遺傳學(xué) Chapter 6 The Basic Patterns of Single Gene Inheritance Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive Y-linked In

3、heritance 4 醫(yī)學(xué)遺傳學(xué) Chapter 6 5 Online Mendelian Inheritance in Man (OMIM) OMIM is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and updated daily. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicin

4、e, Johns Hopkins University School of Medicine, under the direction of Dr. Ada Hamosh. 醫(yī)學(xué)遺傳學(xué) Chapter 6 Number of Entries 6 醫(yī)學(xué)遺傳學(xué) Chapter 6 PrefixAutosomal X Linked Y Linked MitochondrialTotals (*)Gene description 14,257702483515,042 (+)Gene and phenotype, combined 8220286 (#)Phenotype description, m

5、olecular basis known 4,2302984294,561 (%)Phenotype description or locus, molecular basis unknown 1,508129501,642 Other, mainly phenotypes with suspected mendelian basis 1,706112201,820 Totals 21,7831,243 596623,151 7 醫(yī)學(xué)遺傳學(xué) Chapter 6 Chrom. Count Chrom.Count 11,54213292 298214509 383615466 460316633

6、571217904 691018236 773419972 855120402 959221163 1056922360 11958X833 12823Y53 OMIM Synopsis of the Human Gene Map (October 5th, 2015) 8 Total number of phenotypes* for which the molecular basis is known 5,588 Total number of genes with phenotype-causing mutation 3,452 OMIM Morbid Map Scorecard (Up

7、dated October 5th, 2015) : 醫(yī)學(xué)遺傳學(xué) Chapter 6 Symbols are used to illustrate the various states and relationships of the family tree 9 醫(yī)學(xué)遺傳學(xué) Chapter 6 Pedigrees : They are graphic representations of a family tree which show the biological relationship of the proband (先證者先證者) to the rest of the individu

8、als. Differ from “Genogram” 10 醫(yī)學(xué)遺傳學(xué) Chapter 6 11 Pedigree analysis - When If more than one individual in a family is affected with a disease, it is a clue that the disease may be inherited. A doctor needs to look at the family history to determine whether the disease is indeed inherited or not. If

9、it is, to establish the mode of inheritance. This information can then be used to predict recurrence risk in future generations. 醫(yī)學(xué)遺傳學(xué) Chapter 6 12 Pedigree analysis - How u Information of family members more than three generation u Information verified by genetic consultant u Investigating the deat

10、h cause, death age, consanguineous marriage, fetal death, abortion, neonatal death u Determining the mode of inheritance: dominant, recessive, sex-linked, autosomal, et al. u Prediction of the probability of an affected offspring 醫(yī)學(xué)遺傳學(xué) Chapter 6 常染色體顯性遺傳常染色體顯性遺傳 Part 1 Autosomal Dominant Inheritance

11、 13 醫(yī)學(xué)遺傳學(xué) Chapter 6 14 醫(yī)學(xué)遺傳學(xué) Chapter 6 15 Bent little fingerEarlobe Hand clasping Tongue rolling 醫(yī)學(xué)遺傳學(xué) Chapter 6 Example 1.1.遺傳與性別無(wú)關(guān)，男女受累的遺傳與性別無(wú)關(guān)，男女受累的 機(jī)會(huì)均等機(jī)會(huì)均等 2.2.患者父母必有一方受累患者父母必有一方受累 3.3.每代都可出現(xiàn)患者，在連續(xù)世每代都可出現(xiàn)患者，在連續(xù)世 代中呈垂直分布。偶爾由于外顯代中呈垂直分布。偶爾由于外顯 不足而出現(xiàn)隔代遺傳的現(xiàn)象不足而出現(xiàn)隔代遺傳的現(xiàn)象 4.4.雙親無(wú)病時(shí)，子代一般均正常雙親無(wú)病時(shí)，子代一般均正

12、常 ( (除非新的基因突變除非新的基因突變) ) 16 醫(yī)學(xué)遺傳學(xué) Chapter 6 17 醫(yī)學(xué)遺傳學(xué) Chapter 6 3040歲發(fā)病，也有歲發(fā)病，也有10多歲或多歲或60 歲歲以后發(fā)病以后發(fā)病 有進(jìn)行性不自主的舞蹈樣動(dòng)作，可合并肌強(qiáng)直有進(jìn)行性不自主的舞蹈樣動(dòng)作，可合并肌強(qiáng)直 可出現(xiàn)神經(jīng)癥狀，如抑郁，智能衰退，最終成為癡呆可出現(xiàn)神經(jīng)癥狀，如抑郁，智能衰退，最終成為癡呆 Huntington 舞蹈癥舞蹈癥 Huntingtons chorea 18 醫(yī)學(xué)遺傳學(xué) Chapter 6 uHuntingtin gene (HTT), also called HD and IT15, 4p16.3

13、, CAG (codes for aa Q) repeats in the exon 1 form polyglutamine tract (or polyQ tract) uNormal case 9-34 repeats, patients 37-100 repeats u# of the repeats correlates the age of onset and severity uGenetic imprinting or anticipation (遺傳印記或早現(xiàn)遺傳印記或早現(xiàn)) Mechanism of the Disorder 19 醫(yī)學(xué)遺傳學(xué) Chapter 6 Trinu

14、cleotide (CAG)n polyQ Healthy gene Patient gene 20 醫(yī)學(xué)遺傳學(xué) Chapter 6 21 醫(yī)學(xué)遺傳學(xué) Chapter 6 Toxicity of HTT-polyQ Pathobiological Change 22 醫(yī)學(xué)遺傳學(xué) Chapter 6 23 醫(yī)學(xué)遺傳學(xué) Chapter 6 24 uUnclear, essential for development, and absence of huntingtin is lethal in mice uhighly expressed in neurons and testes in huma

15、ns and rodents uupregulates the expression of Brain Derived Neurotrophic Factor (BDNF) , not know how uprimarily associated with vesicles and microtubules, indicating a functional role in cytoskeletal anchoring or transport of mitochondria Function of HTT 醫(yī)學(xué)遺傳學(xué) Chapter 6 More CLINICALMore CLINICAL E

16、XAMPLESEXAMPLES Familial hypercholesterolemia (家族性高膽固醇血癥家族性高膽固醇血癥) Polysystic kidney disease,adult (成年多囊腎病成年多囊腎病) Alpha- thalassemias (-地中海貧血地中海貧血) Brachydactyly, type A1 短指短指(趾趾)癥癥A1型型 Neurofibromatosis, type 1 (神經(jīng)纖維瘤神經(jīng)纖維瘤) 25 醫(yī)學(xué)遺傳學(xué) Chapter 6 BrachydactylyBrachydactyly, type A1 , type A1 短指短指(趾趾)癥癥

17、A1型型 26 Complete dominance 醫(yī)學(xué)遺傳學(xué) Chapter 6 The phenotype of the heterozygote (Aa) will be intermediate between the phenotypes of the two homozygotes (AA or aa). 27 Incomplete dominance (semidominance) Example: Achondroplasia (MIM 100800) 軟骨發(fā)育不全癥 mutation in fibroblast growth factor receptor 3. The m

18、utated form of the receptor is constitutively active and this leads to severely shortened bones. Heterozygote： 50% chance of passing dwarfism Homozygote： recessive lethal 醫(yī)學(xué)遺傳學(xué) Chapter 6 婚配類型和子代發(fā)病風(fēng)險(xiǎn)婚配類型和子代發(fā)病風(fēng)險(xiǎn) u Genetic testing (Genetic counseling) u Family planning choices A a a a Parent Healthy (a

19、a) Affected (Aa) Phenotype affected healthy Probability Ratio 1 : 1 28 醫(yī)學(xué)遺傳學(xué) Chapter 6 常染色體隱性遺傳常染色體隱性遺傳 Part 2 Autosomal Recessive Inheritance 29 醫(yī)學(xué)遺傳學(xué) Chapter 6 Pedigree Characteristics 30 醫(yī)學(xué)遺傳學(xué) Chapter 6 遺傳與性別無(wú)關(guān)，男女受遺傳與性別無(wú)關(guān)，男女受 累的機(jī)會(huì)均等。累的機(jī)會(huì)均等。 患者為隱性基因純合子，患者為隱性基因純合子， 父母表現(xiàn)正常，但均為致病父母表現(xiàn)正常，但均為致病 基因攜帶者基因攜

20、帶者。 表現(xiàn)正常的子代中有表現(xiàn)正常的子代中有2/32/3的的 概率是攜帶者概率是攜帶者 系譜中無(wú)連續(xù)遺傳現(xiàn)象，系譜中無(wú)連續(xù)遺傳現(xiàn)象， 常為散發(fā)或隔代遺傳。常為散發(fā)或隔代遺傳。 近親婚配的后代中發(fā)病率近親婚配的后代中發(fā)病率 顯著增高。顯著增高。 31 醫(yī)學(xué)遺傳學(xué) Chapter 6 CLINICALCLINICAL EXAMPLESEXAMPLES Albinism (白化癥白化癥) Galactosemia (半乳糖血癥半乳糖血癥) Homocystinuria (高高胱胱氨酸尿癥氨酸尿癥) Cystic fibrosis (囊性纖維化囊性纖維化) Sickle cell anemia (鐮刀

21、型細(xì)胞貧血鐮刀型細(xì)胞貧血) Thalassemia (地中海貧血地中海貧血) Phenylketonuria (苯丙酮酸尿癥苯丙酮酸尿癥) 32 醫(yī)學(xué)遺傳學(xué) Chapter 6 33 醫(yī)學(xué)遺傳學(xué) Chapter 6 Oculocutaneous Albinism Differ from Ocular Albinism, a Mendelian type X-linked recessive disorder OCA: due to absence or defect of tyrosinase, a copper- containing enzyme involved in the produ

22、ction of melanin. It is the opposite of melanism, different from melanoma. Tyrosinase activity is very important to be balanced. Several polyphenols, including flavonoids or stilbenoid, substrate analogues, free radical scavengers, and copper chelators, have been known to inhibit tyrosinase. Hencefo

23、rth, the medical and cosmetic industries are focusing research on tyrosinase inhibitors to treat skin disorders. 34 Oculocutaneous Albinism (OCA) 醫(yī)學(xué)遺傳學(xué) Chapter 6 婚配類型和子代發(fā)病風(fēng)險(xiǎn)婚配類型和子代發(fā)病風(fēng)險(xiǎn) u No consanguineous marriage u Genetic testing (Genetic counseling) u Family planning choices A a A a Parent Carrie

24、r (Aa) Carrier (Aa) Phenotype healthy affected Probability 3/4 1/4 Ratio 3 : 1 If parents are Aa x aa ? Or AA x Aa ? Or AA x aa ? Or aa x aa ? 35 醫(yī)學(xué)遺傳學(xué) Chapter 6 X 連鎖的顯性遺傳連鎖的顯性遺傳 part 3 X-linked Dominant Inheritance 36 醫(yī)學(xué)遺傳學(xué) Chapter 6 1.1.致病基因在致病基因在X X染色體上，患者父染色體上，患者父 母中必有一方為受累者。母中必有一方為受累者。 2.2.每代都可

25、出現(xiàn)患者，象每代都可出現(xiàn)患者，象ADAD那樣垂那樣垂 直分布。直分布。 3.3.女性患者的子女中女性患者的子女中1/21/2為患者，為患者， 男性患者只將疾病傳給女兒。男性患者只將疾病傳給女兒。 4.4.女性患者多于男性，且臨床癥狀女性患者多于男性，且臨床癥狀 較輕較輕。女性雜合子患者常流產(chǎn)。女性雜合子患者常流產(chǎn)。 系譜特征系譜特征 37 醫(yī)學(xué)遺傳學(xué) Chapter 6 38 醫(yī)學(xué)遺傳學(xué) Chapter 6 抗維生素抗維生素D D性佝僂病（性佝僂?。╒itamin D resistant rickets） 低磷酸鹽血癥，血清磷下降低磷酸鹽血癥，血清磷下降50%50%，尿磷增多。，尿磷增多。 男

26、性嚴(yán)重，下肢出現(xiàn)畸形，女性骨骼畸形多不嚴(yán)重；一周男性嚴(yán)重，下肢出現(xiàn)畸形，女性骨骼畸形多不嚴(yán)重；一周 歲發(fā)病，開(kāi)始為歲發(fā)病，開(kāi)始為型腿表現(xiàn)。型腿表現(xiàn)。 大大劑量劑量VitD不能不能糾正發(fā)育異常。糾正發(fā)育異常。 腎小管對(duì)磷的重吸收降低引起。腎小管對(duì)磷的重吸收降低引起。 致病基因致病基因 PHEX 位于位于 Xp22。 Clinical Example 39 醫(yī)學(xué)遺傳學(xué) Chapter 6 Vitamin D Resistant Rickets also called X-linked hypophosphatemia Vitamin D Resistant Rickets (XLH, MIM 30

27、7800) 40 醫(yī)學(xué)遺傳學(xué) Chapter 6 41 uPHEX regulates fibroblast growth factor 23, encoded by FGF23 gene. uFGF23 normally inhibits the kidneys ability to reabsorb phosphate into the bloodstream. uMutations of PHEX, resulting overactivity of this protein, reduces phosphate reabsorption by the kidneys, leading

28、to hypophosphatemia. uIn the absence of PHEX enzymatic activity, osteopontin (骨 橋蛋白) may accumulate in the bone to contribute to the osteomalacia (骨軟化癥) in mice. XLH 醫(yī)學(xué)遺傳學(xué) Chapter 6 第四第四節(jié)節(jié) X 連鎖的隱性遺傳連鎖的隱性遺傳 Part 4 X-linked Recessive Inheritance 42 醫(yī)學(xué)遺傳學(xué) Chapter 6 1. 1.致病基因位于致病基因位于X X染色體上，男染色體上，男 性患者顯

29、著多于女性患者。性患者顯著多于女性患者。 2. 2. 呈交叉遺傳。男性患者把致病呈交叉遺傳。男性患者把致病 基因通過(guò)雜合子女兒傳給他們半基因通過(guò)雜合子女兒傳給他們半 數(shù)的兒子，可出現(xiàn)隔代遺傳現(xiàn)象。數(shù)的兒子，可出現(xiàn)隔代遺傳現(xiàn)象。 3.3.攜帶者攜帶者女性女性與正常男性婚配，與正常男性婚配， 男孩每胎得病概率為男孩每胎得病概率為0.50.5。男性。男性 患者與正常女性婚配，子女都正患者與正常女性婚配，子女都正 常，女孩必為攜帶者。常，女孩必為攜帶者。 4.4.家系中患者呈斜行分布，舅父家系中患者呈斜行分布，舅父 和外甥受累。男性和外甥受累。男性患者不患者不會(huì)會(huì)把把此此 病傳給兒子。病傳給兒子。 系

30、譜特征系譜特征 43 醫(yī)學(xué)遺傳學(xué) Chapter 6 44 醫(yī)學(xué)遺傳學(xué) Chapter 6 CLINICAL EXAMPLES 色盲色盲 眼白化病眼白化病 無(wú)丙種球蛋白血癥無(wú)丙種球蛋白血癥 G- 6 - PD G- 6 - PD 缺乏癥缺乏癥 腎性尿崩癥腎性尿崩癥 血友病血友病 B B 睪丸女性化睪丸女性化 先天性高尿酸血癥先天性高尿酸血癥 粘多糖累積癥粘多糖累積癥 型型 肌營(yíng)養(yǎng)不良癥（肌營(yíng)養(yǎng)不良癥（Becker Becker 型、型、 Duchenne Duchenne 型型 ) ) 慢性肉芽腫病慢性肉芽腫病 無(wú)汗型外胚層發(fā)育不良癥無(wú)汗型外胚層發(fā)育不良癥 45 醫(yī)學(xué)遺傳學(xué) Chapter 6

31、 u Bleed for a longer time than others after an injury u Bleed internally, especially in knees, ankles, and elbows Chromosome: Xq28 Gene: coagulation factor VIIIc 46 醫(yī)學(xué)遺傳學(xué) Chapter 6 47 Prince Albert Queen Victoria (MIM 306700) 醫(yī)學(xué)遺傳學(xué) Chapter 6 48 Duchenne muscular dystrophy Duchenne肌營(yíng)養(yǎng)不良肌營(yíng)養(yǎng)不良 uCaused

32、 by a mutation in the gene dystrophin （DMD）, Xp21.2 uDMD is an important component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane uWhile both sexes can carry the mutation, females are rarely affected. 醫(yī)學(xué)遺傳學(xué) Chapter 6 49 DMD Y連鎖遺傳連鎖遺傳(Y-

33、linked inheritance) 決定某種性狀或疾病的基因位于決定某種性狀或疾病的基因位于Y染色體上，只要染色體上，只要Y 染色體上有此基因，即可表現(xiàn)出相應(yīng)的性狀。染色體上有此基因，即可表現(xiàn)出相應(yīng)的性狀。 系譜特征：系譜特征： 具有具有Y連鎖者均為男性，親代男方攜帶此基因只傳給連鎖者均為男性，親代男方攜帶此基因只傳給 全部?jī)鹤?，不傳給女兒，即男全部?jī)鹤?，不傳給女兒，即男-男男傳遞傳遞 (male to male transmission)。 50 醫(yī)學(xué)遺傳學(xué) Chapter 6 1. 1.致病基因致病基因位于位于Y Y染色染色 體體上上，僅限于僅限于男性患者。男性患者。 2. 2. 呈呈

34、垂直垂直遺傳遺傳，父?jìng)髯樱競(jìng)髯印?Pedigree characteristics 51 醫(yī)學(xué)遺傳學(xué) Chapter 6 單基因遺傳病分析中常見(jiàn)名詞單基因遺傳病分析中常見(jiàn)名詞 52 醫(yī)學(xué)遺傳學(xué) Chapter 6 一、外顯率一、外顯率 ( (Reduced penetrance ) ) It is a clinical term which is an expression of the number of individuals who have the gene and show the trait. It is an all or nothing phenomenon and if t

35、he frequency is less than 100 %, reduced penetrance exists. 外顯率外顯率 : : 指在一個(gè)有致病基因（顯性雜合或者隱性純合）指在一個(gè)有致病基因（顯性雜合或者隱性純合） 的群體中得以表現(xiàn)的百分率。完全外顯的群體中得以表現(xiàn)的百分率。完全外顯 100%, 100%,不完全外顯不完全外顯 100 100 %,%,頓挫型頓挫型: :未外顯。未外顯。 53 醫(yī)學(xué)遺傳學(xué) Chapter 6 二、表現(xiàn)度二、表現(xiàn)度（ Variable expressivity ） It refers to the degree of expression of a t

36、rait. The individuals in a family may show mild to moderate to severe forms of the disease and need to be examined carefully in order not to miss the diagnosis. 表現(xiàn)度表現(xiàn)度: :指一種致病基因的表達(dá)程度，與外顯率是質(zhì)與量指一種致病基因的表達(dá)程度，與外顯率是質(zhì)與量 的關(guān)系。輕度的關(guān)系。輕度( (mild)、中度中度( (moderate)、重度重度( (severe)。 54 醫(yī)學(xué)遺傳學(xué) Chapter 6 指一個(gè)基因可以決定或影響多個(gè)

37、性狀指一個(gè)基因可以決定或影響多個(gè)性狀。 三、三、基因多效性基因多效性 ( pleiotropy ) ) 55 醫(yī)學(xué)遺傳學(xué) Chapter 6 四、遺傳異質(zhì)性四、遺傳異質(zhì)性( (genetic heterogeneity) ) A similar clinical picture may be produced by different mutations at the same locus or at different loci. Retinitis pigmentosa may be caused by both autosomal dominant or recessive inheri

38、tance. 遺傳異質(zhì)性遺傳異質(zhì)性: : 是指一種性狀可以有多個(gè)不同的基因控制。是指一種性狀可以有多個(gè)不同的基因控制。 由于遺傳基礎(chǔ)的不同，它們的遺傳方式由于遺傳基礎(chǔ)的不同，它們的遺傳方式 、發(fā)病年齡、病、發(fā)病年齡、病 情進(jìn)展、嚴(yán)重程度、受損部位、預(yù)后以及復(fù)發(fā)率等等，情進(jìn)展、嚴(yán)重程度、受損部位、預(yù)后以及復(fù)發(fā)率等等， 都可能是不同的都可能是不同的。 56 醫(yī)學(xué)遺傳學(xué) Chapter 6 五、五、遺傳遺傳印跡印跡 ( (Genetic Imprinting ) ) Variation in severity dependent on sex . In Huntingtons disease, th

39、e disease manifests earlier, if the affected parent is the father. 遺傳遺傳印跡印跡：指同一基因會(huì)隨著它來(lái)自父源或母源而有不同指同一基因會(huì)隨著它來(lái)自父源或母源而有不同 的表現(xiàn)。這與基因在生殖細(xì)胞形成的過(guò)程中受到不同的修的表現(xiàn)。這與基因在生殖細(xì)胞形成的過(guò)程中受到不同的修 飾有關(guān)，一些遺傳病的表現(xiàn)度與外顯率就受到突變基因遺飾有關(guān)，一些遺傳病的表現(xiàn)度與外顯率就受到突變基因遺 傳傳印跡印跡的影響。的影響。 57 醫(yī)學(xué)遺傳學(xué) Chapter 6 六、六、延遲顯性延遲顯性 (delayed dominance) Variation in a

40、ge onsetVariation in age onset： Adult polycystic Adult polycystic kidney disease although inherited as a dominant kidney disease although inherited as a dominant trait shows cysts only later in life. trait shows cysts only later in life. 延遲顯性延遲顯性 ：帶有顯性基因的個(gè)體有時(shí)在早年并不表現(xiàn)癥狀帶有顯性基因的個(gè)體有時(shí)在早年并不表現(xiàn)癥狀 體征，而到成年才發(fā)病。

41、體征，而到成年才發(fā)病。 58 醫(yī)學(xué)遺傳學(xué) Chapter 6 指一些遺傳?。ㄍǔ轱@性遺傳?。┰谶B續(xù)幾代指一些遺傳?。ㄍǔ轱@性遺傳病）在連續(xù)幾代 的遺傳中，發(fā)病年齡提前而且病情嚴(yán)重程度增加。例如遺的遺傳中，發(fā)病年齡提前而且病情嚴(yán)重程度增加。例如遺 傳性小腦性運(yùn)動(dòng)共濟(jì)失調(diào)（傳性小腦性運(yùn)動(dòng)共濟(jì)失調(diào)（MarieMarie型型) ) 綜合征。綜合征。 七、遺傳早現(xiàn)七、遺傳早現(xiàn) ( (anticipation)anticipation) 59 醫(yī)學(xué)遺傳學(xué) Chapter 6 七、完全顯性七、完全顯性( (complete dominance)complete dominance)：雜合子可以完全表雜合子可以完全表 現(xiàn)出與顯性純合子相同的性狀。如短指癥，現(xiàn)出與顯性純合子相同的性狀。如短指癥，F(xiàn)APFAP。 八八、不完全顯性不完全顯性( (incomplete dominance)incomplete dominance)：又稱中間型顯又稱中間型顯 性或半顯性，指雜合子的表現(xiàn)介于顯性純合子和隱性純合子性或半顯性，指雜合子的表現(xiàn)介于顯性純合子和隱性純合子 之間。如之間。如 - -地中海貧血和人類對(duì)苯硫脲地中海貧血和人類