单基因遗传病高级遗传2012.ppt
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1、单基因遗传病,Single gene disorders Monogenic disorders,Etiology of diseases. For any condition the overall balance of genetic and environmental determinants can be represented by a point somewhere within the triangle.,Classification of Genetic Disorders,Single gene disorders are caused by defects in one p
2、articular gene, and often have simple and predictable inheritance patterns. They affect about 1 per cent of the population as a whole.,Classification of genetic disorders,Multifactorial Variants in genes causing alteration of function Single gene Mutations in single genes (often causing loss of func
3、tion Chromosomal Chromosomal imbalance causes alteration in gene dosage Mitochondrial Somatic mutations (cancer),Male,Recessive Homozygotes with two copies of the altered gene are affected,Dominant Heterozygotes with one copy of the altered gene are affected,X-linked recessive Males with one copy of
4、 the altered gene on the X-chromosome are affected,Multifactorial (common) - “Environmental” influences act on a genetic predisposition to produce a liability to a disease. - One or more organ system affected. - Person affected if liability above a threshold. Single gene (1% liveborn) - Dominant/rec
5、essive pedigree patterns (Mendelian inheritance). - Can affect structural proteins, enzymes, receptors, transcription factors. Chromosomal (0.6% liveborn) - Thousands of genes may be involved. - Multiple organ systems affected at multiple stages in gestation. - Usually de novo (trisomies, deletions,
6、 duplications) but can be inherited (translocations).,Genetic disorders,Single gene disorders: disorders in which inheritance is due to a single mutant gene,Mendelian inheritance Genes are units of heredity, based in DNA Phenotype (physical or functional abnormalities) Genotype (DNA change) 4. Autos
7、omal vs X-linked determined by whether the responsible gene is carried on one of the autosomal chromosomes or on the X chromosome 5. Dominant vs Recessive , based on phenotypic expression,Single gene disorders,- High risks to relatives - Dominant/recessive pedigree patterns - Some isolated cases due
8、 to new dominant mutations - Structural proteins, enzymes, receptors, transcription factors,Characteristics of single gene inheritance,Autosomal Dominant vertical (successive), risk of affected offspring 50% (both sex) Autosomal Recessive horizontal, multiple sibs affected, usually one generation, c
9、onsanguinity (+) risk of affected offspring 25%, carrier 50% X-linked Dominant daughters of affected males (+), sons of affected males (-), affected females transmit the disorder to offspring of both sexes, risk of affected offspring 50%, but twice as many affected females as affected males (no male
10、 to male) X-linked Recessive males through carrier women, males affected almost exclusively, females affected only when affected father and carrier mother or with skewed X-inactivation Y-linked males affected,Characteristics of Autosomal Dominant inheritance 1. The phenotype usually appears in every
11、 generation, each affected person having an affected parent Exceptions : (1)fresh mutation (2)the disorder is not expressed or is expressed only subtly in a person who has inherited the responsible gene. 2. Any child of an affected parent has a 50 percent risk of inheriting the trait 3. both males a
12、nd females are affected in a 1 : 1 ratio,Autosomal dominance inheritance (AD),Pedigree showing typical inheritance of a form of progressive sensorineural deafness (DFNA1) inherited as an autosomal dominant trait,Characteristics of Autosomal Recessive Inheritance 1. An autosomal Recessive phenotype,
13、typically is seen only in the sibship of the proband, not in parents, offspring, or other relatives. 2. both sexes are affected with equal frequency at a ratio of 1:1 3. Parents of an affected child are asymptomatic carriers of mutant alleles. heterozygous parents have a risk of 25% of affected offs
14、pring 4. The parents of the affected person may in some cases be consanguineous. This is especially likely if the mutant gene is rare in the population.,Autosomal Recessive Inheritance (AR),Characteristics of X-linked Dominant Inheritance 1. The incidence of the trait is much higher in females than
15、in males (about twice) ,but affected females typically have milder (variable) expression of the phenotype. 2. Affected males with normal mates have normal sons and Affected daughters. 3. Both male and female offspring of Affected female have a 50 percent risk of inheriting the phenotype. 4.The pedig
16、ree pattern is the same as autosomal dominant inheritance.,X-linked Dominant Inheritance (XD),Characteristics of X-Linked Recessive Inheritance The incidence of the trait is much higher in males than in females. The gene is ordinarily never transmitted directly from father to son (male-to-male), but
17、 it is transmitted by an affected male to all his daughters . A carrier Female for an X-chromosomal mutation has a risk of 50% For an affected son. The gene may be transmitted through a series of carrier females; affected males inherit the mutant allele from the mother only Heterozygous females are
18、usually unaffected, but some may express the condition with variable severity as determined by the pattern of X inactivation,X-linked Recessive Inheritance (XR),Y-linked inheritance,Gene : YA ( mutant allele ) Ya Genotype : XYA XYa holandric inheritance (全男性遗传) male-to-male,Y-linked inheritance,Sing
19、le gene disorders Huntington Disease Myotonic Dystrophy Hereditary Motor Sensory Neuropathy (HMSN) Neurofibromatosis Marfan syndrome Cystic Fibrosis Spinal Muscular Atrophy (SMA) Duchenne Muscular Dystrophy Hemophilia,如何确定所研究的疾病是单基因病? 确认方法主要有以下两种: 1) 参考OMIM(Online Mendelian Inheritance in Man)数据库,根据
20、疾病的表型或者临床症状等确定是否属于OMIM收录的单基因病。 OMIM除了简略描述各种疾病的临床特征、诊断、鉴别诊断、治疗与预防外,还提供已知相关致病基因的连锁关系、染色体定位、组成结构和功能、动物模型等资料,并附有经缜密筛选的相关参考文献。 网址为:http:/omim.org 2) 绘制疾病的遗传系谱图,通过系谱图分析其遗传方式来判断是否属于孟德尔遗传病。 系谱分析法是研究人类遗传规律的重要方法。在临床上,常用系谱分析法来判断某种疾病的遗传方式。系谱图就是从先证者(proband)(家系中第一个被医生确诊的某遗传病的患者,或者具有某种性状的成员)入手,追溯调查其所有家庭成员的数目、亲属关系
21、、某种遗传病(或性状)的分布等资料,按照一定格式绘制而成的图解。,单基因病研究举例及进展,Rieger 综合征(#MIM 180500)致病基因PITX2的研究,Rieger 综合征是Axenfeld-Rieger症候群中最为严重的一型 典型临床表现: 眼前节发育不良,继发青光眼 口颌发育异常: 先天多数牙缺失,过小牙,畸形牙 面中部发育不足,下颌前突等 脐残断回缩异常 遗传方式:常染色体显性遗传,发生率约为1:200,000,临床资料:,家系I 先证者,Rieger综合征相关基因和染色体区域,PITX2 4q25 FOXC1 6p25 PAX6 11p13 13q14,All these R
22、ieger-syndrome-associated genesencode transcription factors and have been shown to play important roles in embryonic development,测 序 结 果,Wild type,1-III:4 cloned,1-III:4 uncloned,家系中的每位患者均存在PITX2基因第5外显子第717-720位ACTT四个碱基的杂合缺失,导致该基因的读码框移位,蛋白质大段功能域缺失,而家系中正常人不存在此突变。,PITX2基因的特征,1996年定位克隆得到同源盒(homeobox) 基
23、因PITX2,编码一种转录因子,属于paired-bicoid基因家族,在发育中高度保守,cDNA编码区与小鼠的同源基因91相同,蛋白质的homeobox区100相同。 Paired-bicoid 的标志是在同源结构域(homeodomain) 第3螺旋50位有一赖氨酸残基,这一残基识别TAAT盒后的CC序列。 小鼠Pitx2参与牙胚的定位,在牙齿发育的较早阶段表达于口腔上皮组织。Pitx2-/- 的小鼠牙胚的发育停止在蕾状期。Pitx2还是心脏形态,上下颌骨的前突,垂体发育所必需的。,PITX2 基因结构图,PITX2的重要功能域,PITX2基因的各种变异剪切体均含相同的homeobox结构
24、域(HD)和C末端,但是N端由不同的外显子组成。 对PITX2分子C端功能的研究提示C端能抑制DNA的结合从而为PITX2与协同因子Pit-1作用创造条件。,PITX2突变谱的总结,15/23的突变发生在HD,7/23的突变发生在HD的3编码区。,图中矩形表示PITX2基因的外显子,标出了翻译的起始(ATG)及终止(TGA)位点。矩形中黑色的区域表示基因的Homeobox结构域。图中的红色星形、三角形、椭圆、圆形、箭头依次表示不同的突变类型:剪切位点突变、缺失突变、点突变、无义突变及插入突变。,PITX2突变功能研究,T68P位于HD第2个螺旋,该突变不改变蛋白质对DNA结合功能,但是使之失去
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