医学遗传学第八章生化遗传病

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,*,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,医学遗传学第八章生化遗传病,What Is Biochemical Genetics?,Biochemical Genetics,是研究基因与酶之间的关系，特别是基因在控制生化代谢过程中各个生物化学反应上的作用的一个学科。,The study of the relationships between genes and enzymes, specifically the role of genes in controlling the steps in biochemical pathways.,Biochemical Genetics,生物化学,是研究体内各个生理反应的化学本质；,遗传学,是研究遗传与变异，是通过变异来研究遗传；而,生化遗传,是研究人体内的各种生物化学变异及其生理学结果。,The Early Landmark Events,Inborn errors of metabolism,One gene,one enzyme,One gene,one polypeptide,血红蛋白病,血浆蛋白病,酶蛋白病,受体蛋白病,膜转运体蛋白病,血 红 蛋 白 病,Hemoglobinopathy,人类生化遗传病是首先从研究血红蛋白病开始,1866,年 胎儿血红蛋白与成人不同,1925,年 地中海区域陆续发现贫血患儿，后来被称作珠蛋白生成障碍性贫血，但习惯称之为地中海贫血,1904,年 一黑人血液中发现了镰形红细胞,1910,年 一例居住在芝加哥的西印度群岛男子患有严重镰形红细胞贫血,历 史 沿 革,1917,年 发现此类贫血患者红细胞在可在体外发生镰变,1927,年 发现缺氧是镰变的重要条件，氧充足时恢复原貌,1949,年,Linus Pauling,等发现正常血红蛋白和镰形血红蛋白电泳速率有异，发表了,镰形红细胞贫血 一种分子病,论文,1956,年，,Ingram,测定出了镰形血红蛋白的氨基酸取代。,全世界异常血红蛋白携带者有,1,亿多人,历 史 沿 革,What is Hemoglobin?,血红蛋白是位于红细胞内的一种由,珠蛋白（,globin,）,和色素辅基,血红素（,heme,）,所组成的一种复合蛋白，在体内担负着携带氧重任。,A hemoglobin molecule consists of four polypeptide chains: two,globin chains,(shown in green and blue) and two,globin chains,(shown in yellow and orange). Each globin chain contains a,heme,(shown in red).,1,2,1,5,3,16pter-p13.3,1 31 32 99 100 141,Hemoglobin Alpha Chain,11p15.5,G,A,1, ,5,3,Hemoglobin Beta Chain,1 30 31 104 105 146,人类血红蛋白的分子结构,血红蛋白（,hemoglobin,）,血红素（,hoem,、,heme,）,珠蛋白（,globin,）,类,链 （, ,）,类,链（, , , ,）,组成人类,6,种血红蛋白,0 2 4 6 8 Birth 2 4 6 8,Months,100,80,60,40,20,Percentage of,globin synthesis(%),Development,of Hemoglobin,Developmental,Stage,Hemoglobin,Hemoglobin Composition,Embryo,Hb Gower1,2,2,Hb Gower2,2,2,Hb Portland,2,G,2,2,A,2,Fetus,Hb F,2,G,2,2,A,2,Adult,Hb A,2,2,Hb A,2,2,2,Development of Hemoglobin,异常血红蛋白病的分子基础,（,1),单个碱基置换,错义突变：如镰形细胞贫血、不稳定血红蛋白病,无义突变：突变为终止密码使肽链合成提前终止,终止密码突变：肽链合成延长,（,2),密码子缺失或插入（,3),移码突变：,插入或缺失的碱基数不是,3,的倍数,（,4),融合基因：,可能在减数分裂时同源染色体之 间错位配对引发不等交换引起两种非同源基 因的部分片段拼接,Sickle Cell Disease (HbS),Missense Mutation,镰形细胞贫血,（,Sickle Cell Anemia,）,Sickle Cell Disease,Sickle Cell Disease,发病机制及临床表现,AR,，血红蛋白,链第,6,位谷氨酸被缬氨酸取代，成为,HbS,，,在脱氧情况下,HbS,聚合成长棒状聚合物，导致血红蛋白溶解度降低，使红细胞镰变。,Sickle Cell Disease,O,2,HbA,HbS,Sickle Cell Disease,Sickle Cell Disease,Sickle Cell Disease,Sickle Cell Disease,纯合子症状严重，由于镰变引起血粘度增高，产生血管阻塞危象，可引起如腹部疼痛、脑血栓等，另有严重溶血性贫血及脾肿大等症状。杂合子不表现临床症状，可以引起红细胞镰变，称为,镰形红细胞性状,(sickle cell trait),。,问题：什么是,HbC,，,HbM,，,Hb Bristol,?,HbS,怎样治疗？如何产前检测,HbS,？,Sickle Cell Anemia (HbS): code 57,Mst,:,CCTNAGG,A,: CCTG,A,GGAG,S,: CCTG,T,GGAG,Sickle Cell Disease,你理解了遗传选择的概念吗？,Thalassemia,Thalassemia,is,inherited anemia caused by decreased synthetic rate of hemoglobin.,Greek letter,designates affected globin chain,: Indicates a gene deletion,/ : Indicates division between genes inherited from both parents,+,: Indicates diminished, but some production of globin chain by gene,0,: Indicates no production of globin chain by gene,Terminology of Thalassemia,Alpha Thalassemia,Alpha thalassemia,occurs when one or more of the four alpha chain genes fails to function.,With alpha thalassemia,the “failed” genes are almost invariably lost due to a genetic accident.,Fusion gene,Codon insertion or deletion,Frame shift mutation,Nonsense mutation,Terminator codon mutation,Pathogenesis,Missense mutation, , , ,G,A,1,5 3,Fusion Gene,Hb Lepore,Difference of beta & delta chain, ,Lepore,Anti Lepore,Fusion Gene,Hb Lepore,Difference of beta & delta chain,Alpha Thalassemia,Types,Genotype,Deletion,Alpha protein,Hemoglobin Barts,0,/,0,/,0,HbH disease,+,/,0,/,25%,Mild anemia,A,/,0, /,50%,+,/,+,/ ,Silent Carrier,A,/,+, / ,75%,Normal,A,/,A, / ,100%,1,2,1,5,3,4.2 Kb,+,thalassemia,Leftward deletion,: The loss of,2, Asian,Rightward deletion,: The loss of,2,(,3,) and,1,(,5,),Pathogenesis,3.7Kb,1,2,1,5,3,0,thalassemia,The loss of,1,2, and 5 end of,1,The loss of,1,2, and,1, Southeast Asia,The loss of,1,2,and,1, Mediterranean sea,The loss of,2,and 5 end of,1, Greeks,Pathogenesis,These occur less commonly than the deletion types.,Pathogenesis,Nondeletion forms of alpha,thalassemia,Beta Thalassemia,Beta thalassemia,occurs when one or two of beta chain genes fails to function.,With beta thalassemia,the beta globin gene is present,but suppressed and produces little beta globin protein,.,Nonfunctional mRNAs,Splice junction mutants,Pathogenesis,Promoter mutants,mRNA capping or tailing mutants,Pathogenesis,Nonfunctional mRNAs,Splice junction mutants,Deletion forms of beta,thalassemia,Pathogenesis,Missense mutation,Nonsense mutation &,Termination codon mutation,Frame shift mutation,Fusion gene,Point mutation in the uncoding region,Pathogenesis,of Hemoglobinopathy,Most,hemoglobin variants are caused by,point mutations,Deletion,Treatment,In both thalassemia and hemoglobinopathy therapy is usually,supportive,rather than curative,Treatment,Chronic blood transfusion,Results in iron overload of major organs resulting in increased morbidity,Laboratory monitoring,Necessitates the use of chelating agents to remove excess iron,Treatment,Alternative treatment,Activation of fetal hemoglobin genes,Bone marrow transplantation,Emphasis,Molecular Disease,Pathogenesis of Abnormal Hemoglobin,Pathogenesis of Thalassemia,先天性的代谢缺陷,（,Inborn errors of metabolism,）,-,尿黑酸尿,（,Alkaptonuria,）,Sir Archibald Garrod pioneering studies on,Alkaptonuria,(,尿黑酸尿,) established the field of biochemical genetics and introduced the concept of the,inborn errors of metabolism.,Genetics of Alkaptonuria,属常染色体隐性遗传，是由于尿黑酸氧化酶基因突变而导致该酶先天性缺乏，使得尿黑酸不能被最终氧化成乙酰乙酸和延胡索酸，造成大量的尿黑酸从尿中排出。而尿黑酸在空气中易被氧化为一种黑色素样的产物而导致尿液逐渐变黑。,该病的发病率约为,1/250 000,，尿黑酸氧化酶基因位于,3q21,q23,。,临床症状,新生儿和儿童期,:,尿黑酸尿是唯一的特点,;,成人期,:,除了尿黑酸尿以外，由于尿黑酸增多，并在结缔组织中沉着，而导致褐黄病（,ochronosis,），如果累及关节的话则进展为褐黄病性关节炎（,ochronotic arthritis,）。,首次在分子水平上对一种疾病的,发病机制进行描述；,将遗传学和医学整合在了一起，提出了该病是先天性的，是遗传的。,Soon everything we understand at the biochemical level we will need to understand in a genetic frame and that will be everything!,One gene,controls the production of,one enzyme,set forth by Beadle and Tatum .,Later it has given way to,one gene-one polypeptide,because of the study of human mutations in intermediary metabolism.,一个基因，一个酶的理论,一个基因，一个多肽的理论,Basic Principles,Basic Principles,Proteins function at every step of metabolic processes,Genes control protein synthesis,Genetic control of metabolic processes introduces human variation,Sometimes that variation results in susceptibility to disease,Sometimes that variation is disease,Case Studies ,Hereditary Enzymopathy,（,遗传性酶病,）,由于基因突变导致酶活性降低或增高所引起的疾病称为先天性代谢病或遗传性酶病。,导致酶活性异常的可能机制,编码特定酶多肽的基因突变造成酶的结构改变而使其功能缺失或增强。,突变涉及调控酶形成速率的基因，引起正常酶数量的不足或增加。,导致酶活性异常的可能机制,酶以较大的速率降解，导致活性酶的不足,(,某些类型的葡萄糖,6,磷酸脱氢酶缺乏）。,酶的最佳活性可能依赖于辅助因子，干扰辅助因子的吸收和生物合成的突变，或是改变酶上的结合位点的突变均可降低酶的活性。,导致酶活性异常的可能机制,酶由两种或多种多肽组成，每个均由独立的基因编码，其中任何一个基因的突变均可引起酶的失活，而且不同的突变位点将会有同样的结果。,S1,S2,S3,P,E,1-2,E,2-3,E,3-P,S6,S7,正常代谢的模式图及发病机制,酶缺乏导致的中间产物堆积和排出，,E2-3,缺乏引起,S2,堆积而在血或尿中浓度增加。,酶缺乏致代谢底物堆积：大多数的酶反应是可逆的，一处的阻断（,E2-3,）常导致底物（,S1,）的堆积。,酶缺乏致代谢终产物缺乏，,E2-3,缺乏引起所有产物的缺乏。,酶缺乏致反馈抑制减弱：某种酶的缺乏导致某些代谢产物的减少，致使该产物对整个反应的反馈调节功能失调。,酶缺乏致旁路产物增多堆积：酶的缺乏导致主要代谢途径受阻，过量的前体物通过旁路代谢引起副产物堆积而引起疾病。,维生素依赖性遗传病：由于基因突变改变了酶蛋白，使之与辅酶的相互作用受到损害而引起酶活性降低，这类辅酶多数是维生素，故称为维生素反应性遗传病。,多种酶缺陷。,酶活性增高引起的遗传性酶病酶活性过高导致产物过多引起的一类疾病称为生产过剩病。,A.,Alkaptonuria,An inherited disorder of metabolism characterized by black urine and degenerative arthritis of the spine and large joints.,Due to the inability to metabolize homogentisic acid due to absence of the enzyme,homogentisic acid oxidase,.,Homogentisic acid in the urine is oxidized to a melanin-like product, which makes urine gradually turn dark.,B.,Phenylketonuria,(PKU),苯丙酮尿症,是由于肝脏中苯丙氨酸羟化酶（,phenylalanine hydroxylase,，,PHA,）,缺乏，从而使苯丙氨酸及其旁路代谢产物在患者的血液和尿中积累所导致的疾病。,该病也是属于,常染色体隐性遗传,，编码,PHA,的两个同源基因如果都发生突变的话，苯丙氨酸就不会被转化为酪氨酸从而累积在体内,人的,PHA,基因定位于,12q22,PKU - What Do Genes Do?,苯丙氨酸,酪氨酸,-,羟,苯丙酮酸,尿黑酸,延胡索酸,乙酰乙酸,PHA,尿黑酸氧化酶,PKU,Alkaptonuria,What will happen for too much phenylalanine,？,过量,的,苯丙氨酸使旁路代谢活跃，产生苯丙氨酸、苯乳酸、苯乙酸等，它们从尿液和汗液排出，使患儿的头发、皮肤和尿均有特殊气味。,What will happen for too much phenylalanine,？,过量,的,苯丙氨酸抑制酪氨酸脱羧酶的活性，影响去甲肾上腺素和肾上腺素的合成，也减少黑色素的合成，使患者毛发和肤色较浅。,What will happen for too much phenylalanine,？,过量,的,苯丙氨酸竞争性的抑制色氨酸羟化作用影响色氨酸的代谢。,此外，旁路代谢产物堆积还抑制,L-,谷氨酸脱羧酶的活性，使氨基丁酸和,5-,羟色胺生成减少，导致脑发育障碍。,临床表现,3,4,个月智力发育不全。,脑电图异常，骨骼发育异常，门齿疏松。,有较严重的呕吐，皮肤、毛发颜色变浅，虹膜颜色减退。,尿、汗有特殊腐臭。,恶性,苯丙酮尿症,四氢生物,蝶呤,是,苯丙氨酸羟化形成酪氨酸过程中所需要的一个辅助因子，其缺乏也将使苯丙氨酸不能羟化形成酪氨酸，致使苯丙氨酸在体内积累引起严重的苯丙酮尿症，称为,恶性苯丙酮尿症,。,恶性,苯丙酮尿症,四氢生物,蝶呤,缺乏还会使多巴、多巴胺、,5-,羟色胺和儿茶酚胺等的浓度降低，从而引起一系列的神经症状。,恶性,PKU,与经典型,PKU,相似，但还可以表现出生时体重低，头围小，流涎，高热，肌张力低等症状。,C.,Albinism,A defect of melanin production, caused by a mutation in a gene,(tyrosinase),coding for a pigment-synthesizing, is characterized by the partial or full absence of pigment from the skin, hair, and eyes.,临床表现：,1.,皮肤白皙，头发淡黄,；,2.,虹膜、瞳孔淡红色或淡蓝色,；,3.,视网膜无色素，,羞明,，视物模糊。,Case Studies ,The Defect in Glucose Metabolism,Galactosemia,半乳糖血症,半乳糖在体内的积累对人体是有害的，能够引起肝肿大，肾衰竭，白内障和脑损伤等严重的综合征，如果不治疗，,75%,的婴儿会死亡。,半乳糖激酶、半乳糖,-1-,磷酸尿苷转移酶和尿苷二磷酸半乳糖,-4-,表异构酶是半乳糖代谢中所涉及的三个主要的酶，任何一个有缺陷均会导致半乳糖血症。,Metabolism of Galactose,半乳糖,-1-,磷酸尿苷转移酶缺乏,半乳糖血症,I,型,导致半乳糖,-1-,磷酸在脑、肝、肾等处积累，出现损伤而致病。,半乳糖,-1-,磷酸尿苷转移酶基因定位于,9p13,，具有多态性。属常染色体隐性遗传。,半乳糖,-1-,磷酸积累,在肝脏引起肝功能损害甚至肝硬化。,在脑中积聚可引起智力低下。,Galactosemia - What Does Gene Do?,半乳糖,-1-,磷酸尿苷转移酶（,9p13,）的基因剂量效应,基因型 酶活性（,%,） 临床表现,G,+,G,+,100,正常,G,+,G,D,75,正常,G,D,G,D,50,正常,G,D,G,G,25,正常,G,R,G,R,10,半乳糖血症,G,G,G,G,0,严重半乳糖血症,1.,喂乳后,几天出现,呕吐,、拒食、腹泻、失重。,2.,一周后，肝脏损害症状：,黄疸、肝肿大、腹水,。,3.,几个月后，智力发育障碍，蛋白尿，氨基酸尿，,白内障,。,半乳糖激酶遗传性缺乏,半乳糖血症,II,型,导致半乳糖在体内积累，导致损伤而致病。,半乳糖激酶,基因定位于,17p21-22,，也属,常染色体隐性遗传。,半乳糖积聚,可使血中葡萄糖释放减少，出现低血糖。,被转变成半乳糖醇，改变晶体状体渗透压，使水分渗入而出现白内障。,尿苷二磷酸半乳糖,-4-,表异构酶遗传性缺乏,半乳糖血症,III,型,患者临床可无症状或者类似经典半乳糖症,B. Glycogen Storage Disease, GSD,糖原累积症,An recessively inherited disorder of glycogen metabolism.,have an inherited absence or deficiency of any of the enzymes responsible for forming or releasing glycogen.,These enzyme defects lead to abnormal tissue concentrations of glycogen or to structurally abnormal forms of glycogen.,糖原贮积症，至少有,13,种类型,临床表现：,进行性肝肾肿大。,乳酸性酸中毒。,严重低血糖、惊厥。,遗传方式：,常染色体隐性遗传为主，,9-11,型,X,连锁隐性遗传。,C. Mucopolysaccharidosis, MPS,黏多糖积累症,黏多糖是由蛋白质和氨基多糖构成的糖蛋白。黏多糖积累症是由于糖苷酶,(glycosidase),或硫酸酯酶,(sulfatase),遗传性缺乏，造成酸性粘多糖部分分解产物如硫酸皮肤素,(dermatan sulfate),和硫酸乙酰肝素,(heparan sulfate),等在各种组织中累积而致病。,黏多糖累积症,7,种类型,（,1,）黏多糖累积症, -H,型,临床表现：,a.,面容粗犷、皮肤粗糙,b.,眼距增宽、鼻梁平塌,c.,肢短掌宽、,关节僵硬,d.,角膜浑浊、智力障碍,生化背景：,-L-,艾杜糖苷酸酶缺乏,遗传方式：常隐,粘多糖累积症,型,临床表现：,a.,表型与,型相似；,b.,无角膜浑浊；,c.,智力障碍较轻；,d.,多毛、进行性耳聋,。,生化背景：,硫酸艾杜糖醛酸酯酶缺乏,遗传方式：,X,隐，,Case Studies ,The Defect in Lipid Metabolism,脂类代谢病是由于脂类分解代谢过程中特异性酶缺乏，导致其相应的脂类底物在内脏、脑部和血管中累积，使这些系统问紊乱而致病，总称脂类累积症,(lipidosis),神经鞘脂累积症,Case Studies ,The Defect in Purine Metabolism,自残综合征,(,Lesch-Nyhan syndrome, LNS,),患者因遗传性缺乏次黄嘌呤鸟嘌呤磷酸核糖基转移酶,(HGPRT),而致病。,HGPRT,催化,5-,磷酸核糖,-1-,焦磷酸,(PRPP),上的磷酸核糖基转移到鸟嘌呤和次黄嘌呤上，使之成为鸟苷酸和次黄苷酸，而它们又可反馈抑制嘌呤前体,5-,磷酸核糖,-1-,胺的生成。 此酶如缺乏，则鸟苷酸和次黄苷酸合成减少，嘌呤合成加快，致使尿酸增高，代谢紊乱而致病。,生化背景：,LNS,为,X,连锁隐性遗传,。,HGPRT,基因定位于,Xq26-q27,。此酶主要的突变类型有：核苷酸取代、插入、缺失和移码突变，可在,DNA,水平上作产前诊断。,临床表现：,1.,高尿酸血和高 尿酸尿症,2.,痛风性关节炎,3.,智力迟钝，大 脑瘫痪,4.,舞蹈样动作，,自残行为,Case Studies ,Receptor Protein Disease,（受体蛋白病）,Familial Hypercholesterolemia, FH,家族性高胆固醇血症,家族性高胆固醇血症,是由于细胞膜上低密度脂蛋白（,low density lipoprotein receptor, LDLR,）缺陷而引起的疾病，表现为人体血浆中胆固醇和甘油三酯的异常堆积，而引起动脉粥样硬化、冠心病和心肌梗死。,ACAT:,脂酰辅酶,A,胆固醇脂酰转移酶,HMG-CoA:,-,羟基,-,甲基戊二酰辅酶,A,还原酶,家族性高胆固醇血症患者因为,LDL,受体缺陷，,LDL,不能进入细胞，使细胞内的胆固醇的反馈抑制受阻，对,HMG CoA,还原酶抑制解除，致使细胞内胆固醇合成增高，血液及细胞内胆固醇堆积而致病。,常染色体显性遗传，患者多为杂合子，,LDL,受体基因定位于。,临床症状,出现角膜弓（老人环）、黄瘤；,过早出现冠心病、心绞痛和心肌梗死；,Case Studies,Hemophilia,（白血病）,:,A bleeding disorder caused by a deficiency in one of the blood clotting factors,Hemophilia A,(often called,classic hemophilia,) accounts for about 80 percent of all hemophilia cases. It is a deficiency in,clotting factor VIII,.,Hemophilia A is caused by an,inherited sex-linked recessive trait,with the defective gene located on the X chromosome. Females are carriers of this trait.,Hemophilia B,(also called,Christmas disease,after Stephen Christmas, a 20th-century British boy who was first diagnosed with it) is a deficiency in clotting factor IX.,Hemophilia B is caused by an,inherited sex-linked recessive trait,with the defective gene located on the X chromosome. Females are carriers of this trait.,Thank You !,不尽之处，恳请指正！,