12遗传病的分子和生化基础睿

1、Chapter 12遗传病的分子和生化基础The Molecular and Biochemical Basis of Genetic Disease黄昱 Huang Yu .cn/medgenetics2013.3.29根据蛋白质的普遍性分类Classes of Proteins according to their generalization 管家蛋白 Housekeeping proteins 所有细胞中都存在，在维护细胞结构和功能中起基本作用 present in virtually every cells and have fundamental roles in maintena

2、nce of cell structure and function特异性蛋白 Specialty proteins 存在于少数细胞种类中，有独特的功能，有助于细胞的异化present in a limited number of cell types, have unique functions that contribute to the individuality of the cells 根据蛋白质的功能分类Classes of Proteins according to their functions酶 Enzymes转运和储存 Transport and storage细胞和器官的

3、结构Structure of cells and organs维持细胞外稳定Extracellular homeostasis发育相关基因表达Development gene expression控制生长和分化 Control of growth and differentiation细胞内代谢和信息 Intercellular metabolism and communicationWe will discuss酶缺陷Enzyme Defects Example: PKU, Lysosomal storage Disease （溶酶体贮积症）受体蛋白缺陷Defects in Receptor

4、 Proteins转运蛋白缺陷Transport Defects结构蛋白缺陷Disorders of Structural Proteins药物遗传疾病 Pharmacogenetic Diseases遗传性酶病Hereditary Enzymopathy 由于基因的突变导致的蛋白酶变异造成的先天性代谢障碍。The inborn errors of metabolism is caused by gene mutation which lead to enzyme protein variants.SubstrateProductPSSPMutant EnzymeExamples of Her

5、editary Enzymopathy疾病Phenylketonuria（PKU）Lesch-Nyhan syndromeTay-Sachs DiseaseMucopolysaccharidoses Hunter syndrome Hurler/Scheie syndrome Sanfilippo syndromeI-cell DiseaseHomocystinuria主要致病基因PAH, Phenylalanine hydroxylaseHprt, Hypoxanthine guanine phosphoribosyltransferaseHex A, Hexosaminidase A id

6、uronate-2-sulphatase -L-iduronidase -D-N-AcetylglucosaminidaseN-acetylglucosaminyl-1-phosphotransferase Cystathionine synthase苯丙酮尿症 Phenylketonuria (PKU) Phenylketonuria (PKU)Phenylketonuria (PKU)云南 一家两个PKU一家两个PKU失察但接受治疗Phenylketonuria (PKU)发病率Incidence: 1 in 16000 in population临床表现Clinical features

7、: Mental retardation 智力障碍 “mousy” odor in urine 鼠尿味 seizure disorder 癫痫 hypopigmentation浅染 of skin and hairPhenylketonuria (PKU)遗传学 Genetics: Autosomal recessive (AR) 苯丙氨酸羟化酶（phenylalanine hydroxylase gene，PAH） 苯丙氨酸phenylalanine 酪氨酸tyrosine病理学 Pathology: Phenylalanine and its derivatives（衍生物） damage

8、 the developing brainPhenylketonuria (PKU)PAHPhenylketonuria (PKU)phenylalaninetyrosinePSSPPAH Mental retardation 智力障碍 “mousy” odor in urine 鼠尿骚味 seizure disorder癫痫 hypopigmentation浅染 of skin and hairBH4缺乏型 PKU Therapy:Dietary reduction of phenylalanineNewborn screeningNewborn ScreeningNewborn Scree

9、ningNewborn ScreeningNewborn Screening 姐弟都是PKU，姐姐在国内出生失查，移民到日本后，日本政府为两个孩子的费用全部买单 罕见病 Rare Diseases “A disease is rare if fewer than 200,000 people in the United States have it. There are close to 7,000 rare diseases and about 25 million people in the U.S. have one. Many rare diseases are caused by c

10、hanges in genes and are called genetic diseases.” From Medline： 总发病率： 8.3 发病率：200,000/300,000,000 1/1500的为罕见病。 平均发病率：25,000,000/7,000*300,000,000 = 1/120,000Comparison of Newborn Screening between China and USABiotinidase Cystic fibrosisgalactosemia (Classical) （半乳糖血症）Sickle C disease Hearing screen

11、ingCongenital adrenal hyperplasia Congenital hypothyroidism 先天性甲状腺功能减退）Sickle cell disease -thalassemia（地中海贫血）5-oxoprolinuria (pyroglutamic aciduria) Glucose 6 phosphate dehydrogenase 6磷酸葡萄糖脱氢酶Nonketotic hyperglycinemiaBenign hyperphenylalaninemia 我国部分地区开展我国部分地区开展我国部分地区开展我国部分地区开展Carbamoylphosphate s

12、ynthetaseHyperammonemia/ornithinemia/ citrullinemia ProlinemiaEthylmalonic encephalopathyHuman immunodeficiency virus Toxoplasmosis3-Methylcrotonyl-CoA carboxylase Carnitine uptake defect (Carnitine transport defect) Long-chain L-3- hydroxyacyl-CoA dehydrogenase Phenylketonuria/hyperphenylalaninemia

13、Argininosuccinate acidemia Glutaric acidemia type 1 Medium-chain acyl-CoA dehydrogenasePropionic acidemia (Propionyl-CoA carboxylase)我国部分地区开展我国部分地区开展Comparison of Newborn Screening between China and USAComparison of Newborn Screening between China and USABeta ketothiolase (mitochondrial acetoacetyl-

14、CoA thiolase) Homocystinuria (cystathionine beta synthase) Multiple carboxylase (Holocarboxylase synthetase ) Trifunctional protein deficiencyMethylmalonic academia (Vitamin B12 Disorders) 3-Hydroxy 3 methylglutaric aciduria Maple syrup urine diseaseTyrosinemia Type 1Citrullinemia type I (Argininosu

15、ccinate synthetase) Isovaleric acidemia (Isovaleryl-CoA dehydrogenase ) Methylmalonic Acidemia (methylmalonyl-CoA mutase) Very long-chain acyl-CoA dehydrogenaseComparison of Newborn Screening between China and USA2-Methyl-3-hydroxy butyric aciduria Carnitine acylcarnitine translocase Glutaric academ

16、ia Type II Malonic academia (Malonyl-CoA decarboxylase)2-Methylbutyryl-CoA dehydrogenaseMethylmalonic acidemia (Cbl C,D) Galactose epimerase Medium-chain ketoacyl-CoA thiolase3-Methylglutaconic aciduria Citrullinemia type II Galactokinase HypermethioninemiaArginemia (Arginase deficiency)Comparison o

17、f Newborn Screening between China and USACarnitine palmitoyltransferase I Short-chain acyl-CoA dehydrogenaseDefects of biopterin cofactor biosynthesis Carnitine palmitoyltransferase II Isobutyryl-CoA dehydrogenase Tyrosinemia type IIDefects of biopterin cofactor regeneration Dienoyl-CoA reductase Me

18、dium/Short chain L-3-hydroxy acyl-CoA dehydrogenase Tyrosinemia type III甲基丙二酸血症Methylmalonic acidemia (MMA)甲基丙二酸血症Methylmalonic acidemia (MMA)常见的症状： 反复呕吐 嗜睡 惊厥 运动障碍 智力发育障碍 肌张力低下甲基丙二酸血症Methylmalonic acidemia (MMA)诊断性治疗：维生素B12负荷试验 即连续3天肌内注射VitB12 1mg/d 维生素B12有效型：cblC、cblD、cblF型 cblA、cblB型(部分有效) 维生素B12

19、无效型：mut0、mut -型甲基丙二酸血症Methylmalonic acidemia (MMA)甲基丙二酸血症Methylmalonic acidemia (MMA)辅酶钴胺素代谢障碍1. 腺苷钴胺素合成缺陷 线粒体钴胺素还原酶缺乏(cblA) 线粒体钴胺素腺苷转移酶缺乏(cblB)2. 胞浆和溶酶体钴胺素代谢异常引起的腺苷钴胺素和甲基钴胺素合成缺陷(cblC、cblD和cblF)，甲基丙二酸血症Methylmalonic acidemia (MMA)甲基丙二酸血症Methylmalonic acidemia (MMA)methylmalonyl-CoA MutaseMUTmethylma

20、lonyl-CoA epimerase表异构酶变位酶China is still a developing country!溶酶体贮积症 Lysosomal Storage Disease，LSDClathrin-coated 溶酶体的功能溶酶体的主要作用是 细胞内消化: 1、细胞自溶，细胞凋亡 2、细胞免疫，防御作用 3、对某些物质的利用 4、参与分泌过程的调节 5、生殖过程 Classification of LSD糖蛋白 Glycoprotein -mannosidosis, -mannosidosis, Fucosidosis. Aspartylglucosaminuria脂质和神经鞘

21、脂类 lipid and sphingolipid GMI gangliosidosis, Fabry disease , Gaucher disease, Niemann-Pick diseases粘多糖 Mucopolysaccharide Mucopolysaccharidosis (MPS) Other LSDs Neuronal ceroid-lipofuscinoses (NCL), Glycogen Storage disease type II (Pompe)Gaucher diseaseGaucher disease was first described in 1882 b

22、y French physician Philippe Charles Ernest Gaucher after he evaluated the corpse of a 32-year-old woman with an enlarged spleen (one of the disorders distinguishing signs).Glucocerebrosidase( -Glu) deficiency1/40000-60000葡萄糖脑苷脂酶缺陷Gaucher cellsLipid-engorged cells with eccentric nuclei（塞满脂质，核异常）, kno

23、wn as Gaucher cells, accumulate and displace healthy normal cells in bone marrow and visceral organsskeletal deteriorationanemia hepatosplenomegalyaffect the brain and nervous systemTherapy of Gaucher disease-Enzyme Replacement Therapy (ERT)Fabry diasease 弥漫性躯体血管角质瘤 X染色体连锁隐性遗传疾病，对男性的影响比较大。 女性携带者有时可出

24、现疾病的某些症状，但通常较轻微。病理 半乳糖苷酶（-galactosidase )基因(GLA)缺陷引起。 神经酰胺三已糖苷无法被代谢，因而堆积在全身许多细胞内的细胞质及溶酶体内。神经酰胺三已糖苷的主要来源是衰老的红细胞。 神经酰胺三已糖苷堆积在血管内皮细胞内时，使血管壁狭窄 ，多器官受累：肾脏、心脏、脑血管、角膜，周围神经系统。 临床表现 儿童期或青春期起病 1、四肢出现间歇性的烧灼样疼痛，或者感觉异常。 2、阵发性腹痛、呕吐、腹泻、少汗、不明原因高热。 3、青春期前后，皮肤血管角质瘤。为多数紫色针尖大的斑丘疹，主亚分布于脐部、腹股沟和大腿，呈对称性。皮肤病通常随着年龄增加而增大面积，但也不

25、一定出现。 4、脑血管壁的受累可致偏瘫、失语、抽搐等局灶性症状，甚至脑出血。5、心律不齐或者心肌缺氧。 6、肾脏受累较严重，甚至需要透析，至成人期常因肾功能不全而死亡。 7、视网膜血管和眼结合膜血管迂曲扩张。裂隙灯检查可见角膜混浊。 诊断 家族病史 四肢疼痛 皮肤病变 特有的涡状角膜浊斑 尿道沉渣 组织活检中发现充满脂质的细胞 半乳糖苷酶活性检测基因突变分析Am. J. Hum. Genet. 2006; 79: 31-40实际发病率被低估的原因是非典型Fabry病的漏诊典型FabryFabry DiseaseAnderson-Fabry DiseaseDr Johannes FabryDr

26、William Anderson法布雷病，Fabry DiseaseX-linked Lysosomal Storage DisorderDeficiency of - galactosidase A (GLA) More than 250 kinds of GLA DNA mutations Majority of them are point mutationsAccumulation of globotriaosylceramide (Gb3)Fabry病的临床表现儿科男性，不明原因的疼痛 儿童期或青春期起病 四肢出现间歇性的烧灼样疼痛 感觉异常风湿免疫科疼痛无汗或少汗肾病皮肤科弥漫性体

27、部血管角皮瘤 病理科溶酶体内洋葱皮（斑马）样累积物Accumulation of globotriaosylceramide (Gb3)眼科角膜漩涡状混浊特征性晶状体混浊结膜血管和视网膜血管迂曲 肾脏科在肾透析病人中Fabry病占0.1-1%的心脏科在男性左心室肥大患者中Fabry病占3在男性晚发型肥大性心肌病患者中Fabry病占6在女性晚发型肥大性心肌病患者中Fabry病占12神经内科在18-55岁脑中风病人中 Fabry病占3从诊断到筛查姓名性别病例号医院1厘米糖原累积症 Pompe disease缺乏-glucosidase，溶酶体糖原降解缺陷按照发生的年龄也可分为婴儿型:出生后最初几个

28、月表现为快速进展的全身性肌病及肥厚性心肌病。患儿因心肺衰竭于1岁内死亡少年型:于婴儿晚期及儿童发病,早期症状是走路困难,为进行性肌营养不良,无心脏问题。成人发病型: 2040岁发病。为进行性肢带型肌病。诊断：尿检和酶活性测定婴儿型成人型We will discussEnzyme Defects Defects in Receptor Proteins Example: Familial HypercholesterolemiaTransport DefectsDisorders of Structural ProteinsPharmacogenetic DiseasesFamilial Hyp

29、ercholesterolemia家族性高胆固醇血症Clinical features: plasma cholesterol 血浆胆固醇atheromas 粥瘤（粥样斑块）heart diseaseXanthomas 黄色瘤arcus cornea 角膜弓Gene: Low-Density-Lipoprotein ReceptorGenetics: autosomal dominant Michael S. Brown Joseph L. Goldstein1985We will discussEnzyme Defects Defects in Receptor ProteinsTransp

30、ort Defects Example: Cystic Fibrosis（囊性纤维化）Disorders of Structural ProteinsPharmacogenetic DiseasesCystic Fibrosis囊性纤维化1 affected/2500; 1 carrier/25 in CaucasianCFTR, cystic fibrosis transmembrane conductance regulator囊性纤维化跨膜传导调节蛋白Life expectancy of the 30,000 CF patients in U.S.A. is under 30 years

31、. Structure & Function of CFTR Chloride ChannelCystic FibrosisWe will discussEnzyme Defects Defects in Receptor ProteinsTransport DefectsDisorders of Structural Proteins Example: DMD（ 假肥大型肌营养不良症）Pharmacogenetic DiseasesDuchenne Muscular Dystrophy (DMD)1/3300 male birthsMuscle weakness at 3-5 Die of

32、respiratory failure before 20 Serum creatine kinase 血清肌酸激酶X-link reccesiveDMD gene, largest gene,79 exonDystrophin1/3 acquired, 2/3 inherited We will discussEnzyme Defects Defects in Receptor ProteinsTransport DefectsDisorders of Structural ProteinsPharmacogenetic Diseases Example: G6PD deficiency P

33、harmacogenetics由于基因的改变导致机体对药物应答的反应改变deals with the variability in response to drugs that is due to genetic variation.Dietary Selective pressures Pharmacogenetics葡萄糖-磷酸脱氢酶缺乏症Glucose-6-phosphate dehydrogenase (G6PD) deficiencyThe most common disease-producing enzyme defect of humanIncidence: 10 percen

34、t of African-American males Affect 400 million people world-wide.Genetics: X-linked dominante(XD), plete dominante gene location Xq28, 13Basic defect: mutations in the G6PD gene.维持红细胞稳 定(1) 过多的H2O2使Hb链表面半胱氨酸的巯基氧化，4条肽链因接触面不稳而散开。(2) 氧化Hb内部巯基，使Hb变性，形成变性珠蛋白小体（Heinz小体）附着于红细胞膜上。(3)氧化红细胞膜上的巯基，使红细胞易被破坏。(4)N

35、ADPH减少本身也降低了红细胞对H2O2的抵抗性。 男性呈显著酶缺乏。女性杂合子酶活性变异范围大，可接近正常也可显著缺乏。 G6PD基因(Xq28): X连锁不完全显性酶活性2070% -X染色体随机失活 G6PD变异型分类类：酶活性严重缺乏（活性10%） 伴有非代偿性慢性溶血 特点：无诱因，反复出现慢性溶血类：酶活性中度或显著缺乏（活性60%） 表现代偿性溶血性贫血 特点：在诱因作用下，才诱发急性溶血类：酶活性轻度降低或升高（活性60100%， 或100%） 特点：表型基本正常可能引起G6PD缺乏者发生溶血的药物类 别药 物氨基喹啉类伯氨喹啉、氯喹、扑疟喹啉、戊氨喹啉砜类氨苯砜、亚磺氨苯砜、

36、噻唑砜磺胺类氨苯磺胺、磺胺醋酰、磺胺异恶唑、柳氮磺胺吡啶、磺胺对甲氧嘧啶硝基呋喃类呋喃妥因、呋喃唑酮、呋喃西林镇痛药乙酰水杨酸、非那西丁、乙酰苯胺其它维生素K（水溶性同类物）、萘、羧苯磺胺、二巯基丙醇、亚甲兰、乙酰苯肼、苯肼、氨甲苯酸、萘啶酸、新砷凡那明、奎宁、奎尼丁、氯霉素1、Abacavir (Ziagen) and HLA-B*5701 阿巴卡韦（赛进），抗艾滋病药2、Atorvastatin (Lipitor) 阿托伐他汀（力普妥），降血脂药3、Azathioprine (Imuran) and TPMT 硫唑嘌呤（依木兰），免疫抑制剂4、Carbamazepine (Tegretol

37、) and HLA-B*1502 卡巴西平（得理多），抗癫痫药5、Cetuximab (Erbitux) and EGFR 西妥昔单抗（爱必妥），治疗结肠直肠癌药6、Clopidogrel (Plavix) and CYP2C19 氯吡格雷（波立维），抗凝血药及溶栓药 7、Dasatinib (Sprycel) and BCR-ABL 达沙替尼（扑瑞赛），抗白血病药8、Imatinib (Gleevec) and BCR-ABL 伊马替尼（格列卫），抗癌药9、Irinotecan (Camptosar) and UGT1A1 伊立替康（Camptosar）治疗结肠直肠癌药10、Panitumu

38、mab (Vectibix) and KRAS 帕尼单抗，治疗结肠直肠癌药11、Rasburicase (Elitek) and G6PD 拉布立酶，治疗和预防血液恶性肿瘤的肿瘤溶解综合征的作用12、Trastuzumab (Herceptin) and ERBB2 (HER2) 曲妥珠单抗（赫赛汀），抗乳腺癌13、Valproic acid (Stavzor) 丙戊酸，抗癫痫及抗惊厥药14、Warfarin (Coumadin) and CYP2C9, VKORC1 华法林，抗凝药Trastuzumab 曲妥珠单抗 治疗 HER-2阳性乳腺癌 Gefitinib Tablet 吉非替尼 治疗

39、EGFR具有敏感突变的局部晚期或转移性非小细胞肺癌 “Soon there will be no disease called breast cancer,” says Draghia-Akli. Instead, the catch-all term will be replaced by “a large number of rare diseases, each of which causes malignant growth in breast tissue and requires individual treatment”.基因型Genotype 和 表现型PhenotypeThe

40、 genotype is the genetic constitution of a cell, an organism, or an individual (i.e. the specific allele makeup of the individual) usually with reference to a specific character under consideration.基因型是一个细胞，一个器官或者一个个体的基因组成（也就是组成这个个体的特殊等位基因）通常有一个特殊性质作为参考 （没翻译出来） （参考：某一生物个体全部基因组合的总称。它反映生物体的遗传构成，即从双亲获得

41、的全部基因的总和。）A phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior.（表现型是一个个体所有能观察到的特征或特点：形态，发育，生化或生理性质，或行为）基因型Genotype 和 表现型PhenotypeNot all organisms with the same genotype look or act the same way. 有相同基因型表现不一定一样。Not all organisms that look alike necessarily have the same genotype.表现一样的不一定有相同基因型。 genotype + environment