医学遗传学：3基因突变的分子细胞生物学效应

1、03 03 基因突变的分子基因突变的分子 细胞生物学效应细胞生物学效应 cellular effects of gene mutationcellular effects of gene mutation cellular effects of gene mutation 人体疾病是细胞病变的综合反映，而细胞人体疾病是细胞病变的综合反映，而细胞 病变则是细胞在致病因素的作用下，组成细胞病变则是细胞在致病因素的作用下，组成细胞 的若干分子相互作用的结果。生物因素、理化的若干分子相互作用的结果。生物因素、理化 因素和遗传因素都可能通过各种途径影响到细因素和遗传因素都可能通过各种途径影响到细 胞内的

2、成分，从而导致细胞病变。胞内的成分，从而导致细胞病变。 gene mutation results in protein abnormal gene mutation abnormal protein cellular effects phenotype gene mutation results in protein abnormal Mutation mutant protein： nProtein biosynthesis nStructure of protein nProtein cellular location nBinding with Prostheic group/cofa

3、tor n Protein polymerization 1 Mutant protein nprimary abnormalities (原发性损害原发性损害) change the primary structure of protein change the primary structure of protein nsecondary abnormalities (继发性损害继发性损害) interfere with synthesis of polypeptide interfere with synthesis of polypeptide chainchain 突变与疾病的关系突

4、变与疾病的关系 突变涉及的突变涉及的 步骤步骤 原发损害原发损害病例病例继发性损害继发性损害病例病例 核苷酸序列转录、RNA剪切地中海贫血、HPFH转录的调节急性间隙性卟啉症 mRNA翻译地中海贫血翻译的调节急性间隙性卟啉症 多肽多肽链折叠LDL受体突变2型翻译后修饰Ehlers-Danlos综合征 三维空间构象亚单位聚合、 细胞定位 胶原形成缺陷亚单位聚合和亚细 胞定位的调节 Zellweger综合征、I细 胞病 生物学功能蛋白质降解Tay-Sachs病蛋白质降解的调节未知 (1) Effects of protein biosynthesis primary abnormalities -

5、thalassemia -thalassemia（-珠蛋白生成障碍性贫血）珠蛋白生成障碍性贫血） Point mutation transcription interference -globin (-珠蛋白珠蛋白) protein biosynthesis secondary abnormalities 速度速度 Acute intermittent porphyria(急性间隙性卟啉症急性间隙性卟啉症) 血红素的合成与急性卟啉症的发生血红素的合成与急性卟啉症的发生 由调节基因表达的蛋白由调节基因表达的蛋白 决定决定 Accumulation culture most heme synthe

6、sis enzymeseven dysfunctional enzymeshave enough residual activity to assist in . The principal problem in these deficiencies is the accumulation of porphyrins, which are toxic(-氨基氨基-酮戊酸酮戊酸 ALA；胆色素原；胆色素原PBG). The acute, or hepatic, porphyrias primarily affect the nervous system, resulting in abdomin

7、al pain, vomiting, acute neuropathy, muscle weakness, seizures, and mental disturbances, including hallucinations, depression, anxiety, and paranoia. 面容苍白 惧怕阳光 牙齿尖利 不死之身 吸食鲜血 大蒜压邪 n乔治三世(King George ,17381820) n维多利亚女王(Queen Victoria,18191901), 患有急性间隙性卟啉症的英王乔治患有急性间隙性卟啉症的英王乔治 (2)Structure of protein ke

8、ratosis palmaris et plantaris(掌跖角化症掌跖角化症) gene mutation: KRT 9 primary abnormalities Structure of protein secondary abnormalities post-translational modification Alzheimers disease protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated pr

9、otein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated. 2. Microtubule (3) Protein subcellular localization Methylmalonic aciduria（甲基丙二氨酸尿症）甲基丙二氨酸尿症） The inherited forms of methylmalonic acidemia cause defects in the metabolic pathway where methylmalonyl-coenzyme A(CoA)（甲基丙酰（甲基丙酰

10、CoA ）is converted into succinyl-CoA（琥珀酰（琥珀酰CoA） by the enzyme methylmalonyl-CoA mutase（甲基（甲基 丙二酰辅酶丙二酰辅酶A羧基变位酶）羧基变位酶） primary abnormalities n体内甲基丙二酰辅酶A、甲基丙二酸、丙酸等 有机酸蓄积，造成一系列神经系统损害 nAcidotic coma nReduced muscle tone nLethargy nDevelopmental delay nUnusual facial appearance nSmall head nConvulsions nM

11、egaloblastic anemia nLeukopenia nMultiorgan failure nHeart muscle disease nRetinopathy nHemolytic uremic syndrome nPsychiatric disorders nNeurological deterioration nMental retardation nBlood abnormalities nSpinal degeneration nHigh levels of homocystine in urine nHigh levels of methylmalonic acid i

12、n the urine nHigh levels of methylmalonic acid in the blood Protein subcellular localization I cell disease (I-细胞病细胞病) ) I cell disease is part of the lysosomal storage disease, family and results from a defective phosphotransferase (an enzyme of the golgi apparatus). The golgi apparatus is unable t

13、o target the lysosomal protein to the lysosome. Without proper functioning of N-acetylglucosamine-1-phosphotransferase（N-乙酰葡萄糖胺乙酰葡萄糖胺 磷酸转移酶）磷酸转移酶）, a build up of substances occurs when enzymes are unable to travel inside of the lysosome. The enzymes are constitutively secreted outside of the cell in

14、stead. These substances or waste products, thought to include carbohydrates, lipids, and proteins, accumulate into masses known as inclusion bodies. secondary abnormalities clinical effect of I-cell disease nabnormal skeletal ndevelopment restricted joint nmovement coarse facial features n Children

15、with ML II usually have enlargement of certain organs, such as the liver,spleen ,or heart (4)Protein polymerization Primary abnormalities Ehlers-Danlos syndrome Mutations alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure a

16、nd strength to connective tissue throughout the body. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder. Mutations (COL1A1, COL1A2, COL3A1, COL5A1, COL5A2)alter the structure of collagen. Protein polymerization

17、secondary abnormalities Ehlers-Danlos syndrome Some type are induced by the mutation of enzymes (ADAMTS2),it alter the processing of the interaction of collagen. Ehlers-Danlos syndrome (5)Binding with Prostheic group/cofator Homo cystinuriaHomo cystinuria（同型胱氨酸尿症）（同型胱氨酸尿症） Mutation results in disord

18、er of Mutation results in disorder of cystathionine synthase (cystathionine synthase (胱硫醚合成胱硫醚合成 酶酶)binding with pyridoxal phosphate()binding with pyridoxal phosphate(磷酸磷酸 吡哆醛吡哆醛).). primary abnormalities 维生素B6 (6)Protein stability Tay-Sachs病病(神经节苷脂GM2积聚) 2 Effect of Protein Function induced by Gene

19、 Mutation nLoss-of-function nGain-of-function nNovel property mutation 凝血因子缺乏 Hemophilia A nLoss-of-function nGain-of-function nNovel property mutation Von willebrand Von willebrand 病病，vWFvWF与与 血小板结合的功能加强，不血小板结合的功能加强，不 易从血小板上分离，患者损易从血小板上分离，患者损 伤时，带有伤时，带有vWFvWF的血小板的的血小板的 凝血作用减弱。凝血作用减弱。 nLoss-of-funct

20、ion nGain-of-function nNovel property mutation nDominant negative effect 甘氨酸 nHeterochronic gene expression / ectopic gene expression 突变对蛋白功能的效应突变对蛋白功能的效应 3 The relationship between the site of a proteins expression and the site of disease nHousekeeping proteins, which are present in virtually every

21、 cell and have fundamental roles in maintenance of cell structure and function nSpecialty proteins, which are produced in only specific tissue and have unique functions nMutation in a tissue-specific protein most often produces a disease restricted to that tissue, also,it can secondary effects on ot

22、her tissues 4 relationship between mutant protein and phonotype nDifferent mutation of same gene produce different clinical phonotype nThe clinical phonotype produced by gene mutation is not clear gene mutation results in phenotype change-cellular effect nInborn errors of metabolism (hereditary enzy

23、mopathy) nMolecular disease 1 Enzyme deficiencies (1)gene mutation results in enzyme defects nStructure abnormalities loss of enzyme activities instability chemical affinity with substrate decrease chemical affinity with cofactor decrease nBiosynthesis abnormalities 酶的生成和体内酶促反应酶的生成和体内酶促反应 (2)Enzyme

24、defect metabolism disorder hereditary disease The disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components. nDeficiency of transport enzyme tryptophan oxidase deficiency(色氨酸加氧酶缺乏症色氨酸加氧酶缺乏症) Incoordination(小脑运动失调) Pachulosis(皮肤粗糙) Hyp

25、erpigmentation(色素沉着) 烟酰胺是辅酶烟酰胺是辅酶I和辅酶和辅酶II的的 组成部分，成为许多脱氢组成部分，成为许多脱氢 酶的辅酶。缺乏时可影响酶的辅酶。缺乏时可影响 细胞的正常呼吸和代谢而细胞的正常呼吸和代谢而 引起糙皮病。引起糙皮病。 色氨酸代谢示意图色氨酸代谢示意图 n accumulation of substances which are toxic or interfere with normal function galactosemia （半乳糖血症）（半乳糖血症） 体内半乳糖代谢途径体内半乳糖代谢途径 naccumulation of coproduct whi

26、ch produced by secondary metabolic pathway Phenylketonuria，PKU（苯丙酮尿症）（苯丙酮尿症） nProduct deficiency albinism（白化病）（白化病） 苯丙氨酸与酪氨酸代谢苯丙氨酸与酪氨酸代谢 1 1 苯丙酮尿症苯丙酮尿症 2 2 尿黑酸尿症尿黑酸尿症 3 3 白化病白化病 nInterfere feedback inhibition 肾上腺皮质激素的合成肾上腺皮质激素的合成21-羟化酶羟化酶 21-羟化酶(21-hydroxylase)的缺陷，使孕酮 (corporin)和17-羟孕酮(hydroxyprogesterone) 不能转化为醛固酮(aldosterone)和可的松 (cortadren)等盐皮质激素(mineralocorticoid)与 糖皮质激素(glucocorticoid) ，却形成大量的 (androstenedione)雄烯二酮和睾酮 (testosterone)。由于血中皮质激素的缺乏，可 负反馈性地促使垂体分泌过量的促肾上腺皮质激 素(ACTH)，使肾上腺皮质增生。结果并不能增加 皮质激素的合成，而继续使睾酮等性激素大量合 成 。 congenital adrenal cortical hyperplasia(先天性先天性 肾上腺皮