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1 单基因遗传病 Monogenic Diseases Shangzhi Huang Peking Union Medical College The WHO Collaborating Centre for Community Control of Hereditary Diseases :00 16:45

2 疾病发生中的遗传因素和环境因素遗传因素环境因素

3 Genes Play an Important Role In All Human Disease

4 Patterns of Human Inheritance Monogenic, rare diseases Mundelein Autosomal dominant Autosomal recessive X- linked Non-Mendelian Y-linked Mitochondrial diseases Multifactorial Common diseases Somatic diseases Chromosomal

5 染色体基因等位基因等位基因核型同源染色体区带基因

6 等位基因 (allele) 同一基因座的不同形式或多态性 DNA 标记位点的多态性 DNA 片段, 彼此称为等位基因 (allele) ε G γ A γ δ ψ β β 11p15.5β 基因簇 ε G γ A γ δ ψ β β 5 5 3' 3'

7 基因突变类型 : 基因突变在遗传物质的改变上, 无非两种情况 : 量 (DNA 长度增加或减少 ) 质 ( 核苷酸的取代 ) 后果 : 导致基因功能异常的突变称为致病突变 (disease-producing mutation), 不引起基因功能改变的称为多态性 (natural variation 或 DNA polymorphisms)

8 表现型与基因型人们通常观察到的是个体的表现型 (phenotype) 基因型 (genotype) : 个体在一个基因座上两个等位基因的组成类型 ; 基因型决定表型, 取决于两个等位基因在表型产生中的作用是否相同 ( 显隐性 )

9 Genotype Definition:The genetic constitution of an individual cell or organism. Homozygous: two identical alleles at a locus Functionally(normal,mutant) Structurally( identical sequence ) Heterozygous: two different alleles at a locus, usually one mutant & one wild-type Compound heterozygous: two different alleles, both usually mutant at a locus Double heterozygous: heterozygous at two different loci

10 Phenotype Definition: The observable character of a cell or organism Dominant vs recessive Dominant: Mutation of one gene copy (allele) that results in a disease phenotype; Recessive: Mutation of both alleles of the gene which gives rise to a disease phenotype; Co-dominant: character expressing for both alleles of the heterozygote

11 ABO 血型的基因型表型 I A I B i 基因型 I A A I A I A I A I B I A AB i A I B I B I A I B I B I B AB B i B i A i I A i I B i B i O 等位基因 : I A I B i, I A I B 相对于 i 为显性 ; I A 与 I B 为共显性 ;i 为隐性

12 Hereditary pattern of disease Denpends on Which chromosome it located The dominant or recessive of the alleles

13 等位基因 T 在家系中的传递 T t T t T t T T t t T t

14 世代传递的是等位基因父母只将其 ½ 遗传物质传递给子代 ( 男性特殊, X 染色体传给女儿 Y 染色体传给儿子 ) 从祖先传递给后代而共享的遗传物质被逐代稀释 ( ½ n ) 共享的染色体区域越来越短 ( 不断互换的结果 ) 姓氏中男性唯一保持不变的是 Y 染色体线粒体由女性传递性状 ( 疾病, 表型 ) 不一定世代传递 ( 取决于基因型, 显隐性 )

15 Hereditary pattern of disease 世代传递着的是基因突变而不是疾病孟德尔遗传非孟德尔遗传染色体常染色体性染色体线粒体显性 AD X XD Y P M 隐性 AR XR

16 Autosomal dominant disease Gene located on the chromosomes 1 to 22, the heterozygote is affected, Homozygous case is rare, the phenotype is more several than heterozygote.

17 显性疾病 : T t t t Ex: 家族性高胆固醇血症 (N+M) 2 =N 2 +2NM+M 2 t t T t t t t t T t t t 1/2 1/2 1/2 1/2 tt T t Tt t t t t 3/4 1/4 1/4 TT T t t t

18 Autosomal dominant disease Inheritance from only one parent Vertical transmission Males and females equally affected Affected parent has 50% chance of transmitting the trait to each offspring At least one male to male transmission More severe phenotype associated with higher frequency of sporadic or non-inherited cases

19 Autosomal Dominant Inheritance Molecular pathophysiology Dominant loss of function Dominant gain of function:a mutation that causes inappropriate expression or function of the gene product Dominant negative effect :a mutation which results in a mutant gene product that can inhibit the function of the wild-type gene product

20 Incomplete dominance semidominance:the phenotype is more severe in homozygote (AA) than heterozygote (Aa) Familial hypercholineterinemia

21 家族性高胆固醇血症纯合子 -- 肘部黄色瘤

22 Definition: the heterozygote may express the corresponding phenotype or not express, or expressed at different extent Causes for irregular dominance: Irregular dominance Penetrance 外显率 Expressivity 表现度

23 Penetrance Definition: A term indicating the likelihood that a given gene will actually result in disease. Completed penetrance:the penetrance is 100% decreased penetrance:part of the individuals are affected, but the others are not affected. the highest penetrance are 70~80% the lowest are 20~30%

24 Variable expressivity

25 软骨发育不良发病率 1/10000~40000,80% 为新生突变 99% 病例为 FGFR3 (Ch.4) G380R(98% 为 1138 位 G>A, 1% 为 G>C)

26 新生突变严格意义上的新生突变减数分裂事件个体发育过程中的突变体细胞嵌合生殖腺嵌合 26

27 Autosomal Recessive Inheritance The mutant gene located on chromosomes 1-22, Heterozygote is not affected Homozygote is affected

28 常染色体隐性遗传 : T t 1/50 T t 1/50 Ex: 苯丙酮尿症 TT T t T T t t T t TT Tt 2/3 1/3 1/50 X 1/50 X ¼ 2/3 =1/ /50 T T T t T t TT TT t t T t 1/3 1/3 2/3 X 1/50 X ¼ = 1/600 Tt T t t t 1/3 X 1/3 X ¼ = 1/36

29 Autosomal Recessive Inheritance Ⅰ Characters: Horizontal pattern in a pedigree; Ⅱ Ⅲ 1 Inheritance from both healthy parents; Males and females equally affected; One fourth of the sibling are affected; Offsprings are usually normal, unless the patient is married to a heterozygote; Increased incidence in consanguineous marriage Ⅳ 1/6 2/ 3 1/3

30 苯丙酮尿症

31 Phenylketonuria, PKU I PKU is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity; without dietary restriction of phenylalanine, most children with PKU develop profound and irreversible mental retardation. The incidence of HPA is 1/11144 in China.

32 高苯丙氨酸血症注意代谢通路与遗传异质性的关系新喋呤 PCD 邻羟基苯乙酸苯丙酮酸苯乙胺苯乳酸苯乙酸苯基乙酰谷酰胺

33 BH4 缺陷 BH4 合成缺陷 : 三磷酸鸟苷环化水解酶 (guanosine triphosphate cyclohydrolase,gtpch) 缺陷 ; 6- 丙酮酰四氢生物喋呤合成酶 (pyruvoyl tetrahydrobiopterin synthase,ptps) 缺陷 ; BH4 循环缺陷 : 二氢生物喋啶还原酶 (dihydropteridine reductase,dhpr) 缺陷 ; 喋呤 -4α 甲醇胺脱水酶 (pterin-4 a carbinolamine dehydratase,pcbd1) 缺陷常染色体隐性遗传 BH4 还参与酪氨酸色氨酸羟化反应和儿茶酚胺五羟色胺含氮氧化物生物合成故该型患者症状更重, 得名恶性

34 中国人 BH4 诊断地区 PAH BH 4 /HPA 发病率 * 比例 PTS 缺陷台湾 1/31,000 19% * 广州 1/33,000 20% 上海 1/17, ~ 16% 北京 1/11,000 6 ~ 7% DHPR 缺陷台湾 (2 个家庭,3 个患者 ) * 根据新生儿筛查数据最新研究显示 : 上海 PTPSD 占 97% 肖广仁

35 软孩

36 SMN 基因两个基因有高度的同源性, 都广泛表达, 选择性剪接产生较小的异型体 : SMN1 全长有功能的 1.7 kb mrna (~90%) 缺外显子 5 (10%) SMN2, 因外显子 7 +6 位 C T 取代, 导致选择性剪接而使外显子 7 跳越, 失去功能转录本缺外显子 5 或 7; 转录本缺外显子 5 和 7 全长 SMN mrna ( 20-30%)

37 SMN1 基因突变 90~98% 的患者纯合缺失外显子 7( 大部分还缺失外显子 8); 错义突变还有一些微小的缺失和重复

38 X-linked Inheritance Male is hemizygous, and is always affected No male to male transmission Heterozygous females nearly always affected, if XD unffected, if XR Females typically less severely affected than males

decreased absorption of calcium and phosphorous from the GI tract; diff dx: - metaphyseal chondrodysplasia

39 X 连锁显性遗传病 X- 连锁低磷酸血症 (hypophosphatemia, 抗维生素 D 佝偻病 ) patholophysiology: - decreased reabsorption of phosphate by the renal tubule (causing hypophosphatemia) (otherwise the renal function is normal); - decreased absorption of calcium and phosphorous from the GI tract; diff dx: - metaphyseal chondrodysplasia - hypophosphatasia: - in contrast to vitamin D resistant rickets, hypophosphatasia shows a reduction in serum alk phos;

40 Hemizygous lethal in males Only females affected Affected females have fewer sons than expected Half of the daughters are affected Affected females have increased frequency of spontaneous abortions Example: 色素失调病和 Goltz 综合征

41 X 连锁隐性遗传病 X 连锁隐性遗传病 T T t EX:DMD EX:DMD 不幸的莱昂化 TT T t TT T t T T TT T t TT T T t T TT TT

42 X-linked Recessive Inheritance Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD); Hemophilia A de novo mutation Gonad mosaicism

43 Gowers 征

44 腓肠肌肥大

45 Dystrophin 免疫组化检测正常肌肉患者 Western 印迹杂交

46 D M D 突变类型

47 肌营养不良病的遗传异质性 DMD SMA MD(Myotonic Dystrophy, 强直性肌萎缩 ) 此疾病除了进行性肌无力外, 还有其他特征, 如肌强直 ( 肌肉收缩之后不能松弛, 常发生早发性白内障, 心脏受累, 受累的肌肉有面部前臂和小腿肌肉. 肢带型肌萎缩 (LGMD) 由许多基因缺陷引起面肩肱型肌萎缩 (FSHD) 面部肌肉无力, 患者不能吹口哨, 睡觉时不能闭眼先天性肌病 Congenital Myopathy Nemaline Myopathy. Central Core Disease, Myotubular Myopathy.

48 遗传异质性 (heterogeneity) Definition (1): The same clinical phenotype causing by different loci (locus heterogeneity) There are more than 100 loci responsible for deafness APKD: PKD1(Ch.16) PKD2(Ch4.) PKD3 Definition (2): different mutant alleles of the same locus cause different phentoypes (allele heterogeneity) β hemoglobin gene mutations: abnormal hemoglobins, sickle cell anemia, β thalassemia Osteogenesis imperfecta: mutation of COL1A1 (dominant negative mutation)

49 新生突变来源于外祖父时, 要警惕父源生殖腺嵌合

50 X chromosome inactivation Lyonization Lyon hypothesis (Lyon,1961): most part of one X chromosome in human female is heterochrmatide without genetic activity. X inactivation occurred in the early embryonic stage. The inactivation is random for either X chromosome (paternal or maternal) if they are both normal The daughter cells remain the inactivation pattern Since there are handrens of cells in the embryo when lyonization occurs, all females are composed of two cell lines.

51 Mosaicism Definition: Presence in an individual or a tissue of at least two cell lines that differ genetically

52 Mosaicism Chimera: two cell lines in the same organism resulted in fussing of two zygotes, fertilizing eggs or egg and the polar body. Mosaic: numberary or structural abnormalities of chromosome caused by chromosome nondisjunction, chromosome loss or intranucleic replication, and chromosome breakage as will as chromosome rearrangement, occuring in early cleavage of the zygote.

53 Y-linked inheritance Male to male transmission Only male are affected

54 Mitochondria disease Heteroplasmic: Mitochondria DNAs are mixture of wide type and mutant DNAs. Maternal inheritance. Replication advantage of defected mitochondria DNA, homoplasmic. Later onset, progressive, and threshold.

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<4D6963726F736F667420576F7264202D20B5DACAAEC1F9D5C22020C1D9B4B2D2C5B4AB2E444F43> 第十六章临床遗传 Chapter 16. Clinical Genetics Clinieal genetics 的主要内容 : Diagnosis, Therapy, Prevention Basis: medical genetics; pedigree investigation; clinical examination 一 The diagnosis of inheritance