分子病与遗传性酶病.ppt

1,分子病与遗传性酶病,2,教科书内容,第一节 分子病 分子病的概念 血红蛋白病 血浆蛋白病 结构蛋白病 受体蛋白病 第二节 遗传性酶病 PKU 溶酶体病 罕见病的概念,3,本次授课内容,分子病 突变对蛋白质功能的影响 例：血红蛋白病 突变导致蛋白质 功能丧失 功能增强 新特性 在错误的时间和/或地点表达 遗传性酶病 例: 苯丙酮尿型，溶酶体贮积症 受体蛋白病 例：家族性高胆固醇血症 结构蛋白病 例：假肥大性肌营养不良,4,Molecular disease,The primary disease-causing event is a mutation, either inherited or acquired.,5,分子病,引起疾病的主要原因是遗传性的或获得性的突变。,Linus Carl Pauling,掌握,6,突变,质,量,蛋白质,DNA,RNA,tRNA,mRNA,疾病,7,突变导致蛋白质 功能丧失 功能增强 新特性 在错误的时间和/或地点表达,突变对蛋白质功能的影响,掌握,8,血红蛋白和血红蛋白病,血红蛋白病是最常见的单基因遗传病 5% carriers in whole population 血红蛋白的结构是最先被解析的 血红蛋白基因是最先被克隆的疾病相关基因 血红蛋白病是在进化和发育过程中研究基因功能的非常好的模型,9,血红蛋白的结构和功能,功能: 在红细胞中氧气的携带者 结构: 四个亚基: 2 2 多肽 + 辅基( 亚铁血红素),280,000,000 Hb/cell,10,11,F8His,E7His,12,13,人类血红蛋白（珠蛋白）基因,基因簇,熟悉,14,珠蛋白基因在发育过程中的表达 以及珠蛋白转换,Hb F (22 , 1%) Hb A2 (22 , 2%),熟悉,15,Beta珠蛋白转座子控制区 （ Locus Control Region，LCR）,LCR是转录的超级增强子,LCR,了解,16,突变导致蛋白质 功能丧失 占较大比例 功能增强 新特性 在错误的时间和/或地点表达,突变对蛋白质功能的影响,掌握,17,是蛋白质功能改变的主要类型 例: -地中海贫血 (- 珠蛋白基因) -地中海贫血 ( - 珠蛋白基因),功能丧失,掌握,18,地中海贫血（Thalassemia） 珠蛋白合成的不平衡,-globin,-globin,-地中海贫血,-globin,-globin,-globin,-globin,正常,-地中海贫血,掌握,19,地中海贫血（-Thalassemias）,-珠蛋白基因 突变或缺失 -globin 相对过剩,掌握,20,-珠蛋白基因的缺失,1.Hb Barts: -/-, 4Hb Barts 胎儿水肿 2.HbH:-/-， ,4(HbH) 沉淀 较严重的溶血性贫血 3. -thalassemia trait: -/or -/- 轻度贫血 4. Silent carrier: -/,21,22,地中海贫血的分子机理,1. 缺失型 常见类型 同源染色体错误配对和不平等交换 2. 非缺失型 少见类型 - 珠蛋白基因点突变,熟悉,23,同源染色体错配和不平等交换,24,同源染色体错配和不平等交换,25, 地中海贫血 -Thalassemias, 珠蛋白基因突变或缺失 珠蛋白相对过剩,掌握,26,27,28,The classic “hair on end“ appearance on plain skull radiographs of a patient with -thalassemia major,29,地中海贫血的分子机理,1. 非缺失型 常见类型 珠蛋白基因突变 2. 缺失型 少见类型,熟悉,30,Therapy of - thalassemia,Blood transfusion + desferrioxamine Splenectomy hematopoietic stemcell trans-plantation Hydroxyurea globin Hb F,了解,31,突变导致蛋白质 功能丧失 功能增强 新特性 在错误的时间和/或地点表达,突变对蛋白质功能的影响,掌握,32,蛋白质功能增强,质的增强 突变导致蛋白质正常功能增强 例:坎普西血红蛋白（Hemoglobin Kempsey） 量的增加 突变导致蛋白质产量增加 例: 21三体综合症（trysomy 21，Down syndrome),熟悉,33,坎普西血红蛋白病,34,35,36,37,突变导致蛋白质 功能丧失 功能增强 新特性 在错误的时间和/或地点表达,突变对蛋白质功能的影响,掌握,38,突变后蛋白质拥有了新特性,突变赋予了蛋白质新的特性，而原有功能不变 例:镰刀型细胞贫血,掌握,39,40,41,GluVal,42,镰刀形血红蛋白纤维 Fibres of Sickle Hemoglobin,43,镰刀形血红蛋白纤维 Fibres of Sickle Hemoglobin,44,镰刀形血红蛋白纤维 Fibres of Sickle Hemoglobin 横截面,45,46,47,48,49,50,Sickle cell disease - therapy,51,突变导致蛋白质 功能丧失 功能增强 新特性 在错误的时间和/或地点表达,突变对蛋白质功能的影响,掌握,52,突变导致蛋白质在错误的时间和/或地点表达 Mutations Associated with Heterochronic or Ectopic Gene Expression,基因调控区改变 蛋白质在错误的时间和/或地点表达 例1: 癌基因 - 癌症 例2: - 珠蛋白 -遗传性胎儿血红蛋白持续增多症,熟悉,53,The War between Human and Malaria,Gene Weapon against Malaria: Sickle cell disease, thalassemia, G6PD deficiency,54,55,蛋白质功能分类,酶 Enzymes 转运和储存 Transport and storage 细胞和器官结构Structure of cells and organs 胞外调节蛋白 Extracellular homeostasis 发育相关 Development gene expression 生长和分化调控Control of growth and differentiation 细胞内代谢和信息传递Intercellular metabolism and communication,56,重点介绍,遗传性酶病Hereditary Enzymopathy 例: 苯丙酮尿型PKU 溶酶体贮积症Lysosomal storage Disease 受体蛋白病Defects in Receptor Proteins 结构蛋白病Disorders of Structural Proteins,57,遗传性酶病Hereditary Enzymopathy,The inborn errors of metabolism is caused by gene mutation which lead to enzyme protein variants.,熟悉,58,遗传性酶病Hereditary Enzymopathy,苯丙酮尿症 PKU Phenylketonuria 溶酶体贮积症 LSD Lysosomal storage disorders,59,苯丙酮尿症 (PKU),60,苯丙酮尿症 (PKU),61,苯丙酮尿症 (PKU),发病率: 1 in 16000 in population 临床表现: 智力障碍, 鼠尿味, 癫痫, 皮肤和毛发浅染 遗传特性: Autosomal recessive (AR), phenylalanine hydroxylase gene (PAH) which converts phenylalanine to tyrosine. 病理特征: 苯丙氨酸及其衍生物损害发育中的大脑,62,63,熟悉,64,治疗：低苯丙氨酸饮食,熟悉,65,新生儿筛查,66,新生儿筛查,67,新生儿筛查,68,新生儿筛查,69,新生儿筛查,70,溶酶体贮积症 (LSD),71,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，形成精子的顶体 ,72,Classification of LSD,Disorders of Glycoprotein degradation: -mannosidosis, -mannosidosis, Fucosidosis. Aspartylglucosaminuria Disorders of lipid and sphingolipid degradation: GMI gangliosidosis, Fabry disease , Gaucher disease, Niemann-Pick diseases, Disorders of Mucopolysaccharide degradation: Mucopolysaccharidosis (MPS) Other Lysosomal Storage Diseases: Neuronal ceroid-lipofuscinoses (NCL), Glycogen Storage disease type II (Pompe),73,74,Gaucher disease,Gaucher disease was first described in 1882 by 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) deficiency 1/40000-60000,了解,75,Gaucher cells,Lipid-engorged cells with eccentric nuclei, known as Gaucher cells, accumulate and displace healthy normal cells in bone marrow and visceral organs skeletal deterioration anemia hepatosplenomegaly affect the brain and nervous system,76,酶替代治疗Enzyme Replacement Therapy (ERT),熟悉,77,78,79,Fabry病 弥漫性躯体血管角质瘤,半乳糖苷酶（-galactosidase )基因(GLA)缺陷引起。 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现疾病的某些症状，但通常较轻微。,了解,80,81,病理,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。,82,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。,83,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,84,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,了解,85,86,Trae I was diagnosed in 1991 at age 22 with AMD. I also have a sister who is severely affected with the disease. She was diagnosed 13 year ago at age 20. In college, I began to notice that it was getting difficult to walk up stairs. I would get very winded, and my muscles would burn. After two muscle biopsies, I was diagnosed with AMD.,After college I married and got pregnant. In my fifth month, I began to have serious problems. I became extremely weak and short of breath and was unable to walk more than about 10 feet. After Haleys birth, I was determined to regain my strength and get off of the Bi-Pap machine. I did regain some strength but was never able to rebuild my pulmonary functions which are now 26% of normal. The disease is still slowly progressing. I have trouble keeping on weight. I have been told that I should not have gotten pregnant. Haley is what my life is all about. She keeps me going and makes me smile on those days when life seems so unfair.,From: ,87,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 changes in genes and are called genetic diseases.” From Medline：/medlineplus/rarediseases.html 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 = 1/120,000,了解,88,中美新生儿筛查项目比较,Biotinidase Cystic fibrosis galactosemia (Classical) Sickle C disease Hearing screening Congenital adrenal hyperplasia Congenital hypothyroidism Sickle cell disease -thalassemia 5-oxoprolinuria (pyroglutamic aciduria) Glucose 6 phosphate dehydrogenase Nonketotic hyperglycinemia Benign 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,89,Carbamoylphosphate synthetase Hyperammonemia/ornithinemia/ citrullinemia Prolinemia Ethylmalonic encephalopathy Human immunodeficiency virus Toxoplasmosis 3-Methylcrotonyl-CoA carboxylase Carnitine uptake defect (Carnitine transport defect) Long-chain L-3- hydroxyacyl-CoA dehydrogenase Phenylketonuria/hyperphenylalaninemia Argininosuccinate acidemia Glutaric acidemia type 1 Medium-chain acyl-CoA dehydrogenase Propionic acidemia (Propionyl-CoA carboxylase),我国部分地区开展,我国部分地区开展,中美新生儿筛查项目比较,90,Beta ketothiolase (mitochondrial acetoacetyl-CoA thiolase) Homocystinuria (cystathionine beta synthase) Multiple carboxylase (Holocarboxylase synthetase ) Trifunctional protein deficiency Methylmalonic academia (Vitamin B12 Disorders) 3-Hydroxy 3 methylglutaric aciduria Maple syrup urine disease Tyrosinemia Type 1 Citrullinemia type I (Argininosuccinate synthetase) Isovaleric acidemia (Isovaleryl-CoA dehydrogenase ) Methylmalonic Acidemia (methylmalonyl-CoA mutase) Very long-chain acyl-CoA dehydrogenase,中美新生儿筛查项目比较,91,2-Methyl-3-hydroxy butyric aciduria Carnitine acylcarnitine translocase Glutaric academia Type II Malonic academia (Malonyl-CoA decarboxylase) 2-Methylbutyryl-CoA dehydrogenase Methylmalonic acidemia (Cbl C,D) Galactose epimerase Medium-chain ketoacyl-CoA thiolase 3-Methylglutaconic aciduria Citrullinemia type II Galactokinase Hypermethioninemia Arginemia (Arginase deficiency),中美新生儿筛查项目比较,92,Carnitine palmitoyltransferase I Short-chain acyl-CoA dehydrogenase Defects of biopterin cofactor biosynthesis Carnitine palmitoyltransferase II Isobutyryl-CoA dehydrogenase Tyrosinemia type II Defects of biopterin cofactor regeneration Dienoyl-CoA reductase Medium/Short chain L-3-hydroxy acyl-CoA dehydrogenase Tyrosinemia type III,中美新生儿筛查项目比较,93,94,95,Tay Sachs Disease的人群筛查工作由以色列卫生部直接资助和执行 1978年开展该项目至今，减少了90Tay Sachs Disease患儿的出生 Gaucher disease虽然携带频率更高，但犹太人多为症状较轻的类型，70以上的家庭不选择产前筛查或中止妊娠。,96,中国Fabry援助中心 /,网站创始人：Jerry 先生 出生年月：1977年8月生 姓名：YaFei Zhang 张亚非 昵称：Jerry 学位：经济学学士 电子信箱： 博客：/yafei1977,97,98,99,有孤儿药法律的国家和地区,US Orphan Drug Act,1983 EC,Regulation No.141/2000 of the European Parliament and of the Council of 16 December 1999 of Orphan Medicinal Products （*涉及欧盟内的20多个国家） Singapore,The medicine (Orphan Drug) exemption order,1991 Japan, Orphan Drug Act,1983 Australia, Orphan Drug Program,1997 台湾，罕见疾病防治及药物法，2000年 古巴，实行全民医保，是世界上医疗保障为完备的国家之一，见下文参考材料：独立特行的卫生厅厅长 巴西，孤儿药品政策见ppt文件Brazilian Experience，另文附上。 此外，亚洲其他国家和地区，如韩国、香港等地也都有孤儿药法规，相关情况请见分析预测:亚洲罕用药物，网址为/free/detail/117948.html,100,China is still a developing country!,101,We are developing!,102,2010罕见病科普宣传活动新闻发布会,2010.2.26,