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1、单基因遗传病高级遗传2012 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望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
2、Single gene disorders are caused by defects in one particular gene,and often have simple and predictable inheritance patterns.They affect about 1 per cent of the population as a whole.Classification of genetic disordersMultifactorial Variants in genes causing alteration of functionSingle geneMutatio
3、ns in single genes(often causing loss of functionChromosomalChromosomal imbalance causes alteration in gene dosageMitochondrialSomatic mutations(cancer)Male+environmentRecessiveHomozygotes with two copies of the altered gene are affectedDominantHeterozygotes with one copy of the altered gene are aff
4、ectedX-linked recessiveMales with one copy of the altered gene on the X-chromosome are affectedMaleMultifactorial(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.S
5、ingle gene(1%liveborn)-Dominant/recessive 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(tr
6、isomies,deletions,duplications)but can beinherited(translocations).Genetic disordersSingle gene disorders:Single gene disorders:disorders in which inheritance is due to a single mutant genedisorders in which inheritance is due to a single mutant gene1.1.Mendelian inheritanceMendelian inheritance2.2.
7、Genes are units of heredity,based in DNAGenes are units of heredity,based in DNA3.3.Phenotype(physical or functional abnormalities)Phenotype(physical or functional abnormalities)Genotype(DNA change)Genotype(DNA change)4.Autosomal vs X-linked4.Autosomal vs X-linked determined by whether the responsib
8、le gene is determined by whether the responsible gene is carried on one of the autosomal chromosomes carried on one of the autosomal chromosomes or on the X chromosome or on the X chromosome5.Dominant vs Recessive,based on phenotypic 5.Dominant vs Recessive,based on phenotypic expression expressionS
9、ingle gene disorders-High risks to relatives-Dominant/recessive pedigree patterns-Some isolated cases due to new dominant mutations-Structural proteins,enzymes,receptors,transcription factorsI:1I:2II:1II:2II:3II:5II:6II:8III:1III:2IV:1 1 1 2 2 1 2 3 1 2 3 4 4 1 1Characteristics of single gene inheri
10、tanceCharacteristics of single gene inheritance Autosomal DominantAutosomal Dominant vertical(successive),risk of affected offspring 50%(both sex)vertical(successive),risk of affected offspring 50%(both sex)Autosomal RecessiveAutosomal Recessive horizontal,multiple sibs affected,usually one generati
11、on,consanguinity(+)horizontal,multiple sibs affected,usually one generation,consanguinity(+)risk of affected offspring 25%,carrier 50%risk of affected offspring 25%,carrier 50%X-linked DominantX-linked Dominant daughters of affected males(+),sons of affected males(-),daughters of affected males(+),s
12、ons of affected males(-),affected females transmit the disorder to offspring of both sexes,affected females transmit the disorder to offspring of both sexes,risk of affected offspring 50%,risk of affected offspring 50%,but twice as many affected females as affected males(no male to male)but twice as
13、 many affected females as affected males(no male to male)X-linked RecessiveX-linked Recessive males through carrier women,males affected almost exclusively,males through carrier women,males affected almost exclusively,females affected only when affected father and carrier mother or with females affe
14、cted only when affected father and carrier mother or with skewed X-inactivation skewed X-inactivation Y-linked Y-linked males affectedmales affected Characteristics of Autosomal Dominant inheritance 1.The phenotype usually appears in every generation,each affected person having an affected parent Ex
15、ceptions:(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 and females are affected in a 1:1 ratio Autosomal dominance inherita
16、nce (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,typically is seen only in the sibship of the proband,not in parents,offspr
17、ing,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 offspring 4.The parents of the affected person may in some cases be consanguineous.Thi
18、s 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 in males(about twice),but affected females typically have milder(variable)expression of
19、 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 pedigree pattern is the same as autosomal dominant inheritance.X-linked Dominant Inheritance (XD)Char
20、acteristics of X-Linked Recessive Inheritance1.The incidence of the trait is much higher in males than in females.2.The gene is ordinarily never transmitted directly from father to son(male-to-male),but it is transmitted by an affected male to all his daughters.3.A carrier Female for an X-chromosoma
21、l mutation has a risk of 50%For an affected son.4.The gene may be transmitted through a series of carrier females;affected males inherit the mutant allele from the mother only 5.Heterozygous females are usually unaffected,but some may express the condition with variable severity as determined by the
22、 pattern of X inactivation X-linked Recessive Inheritance (XR)Y-linked inheritance Gene:YGene:YA A（mutant allele ）Y Ya aGenotype :XYGenotype :XYA A XY Ya aholandric inheritance(holandric inheritance(全男性遗传全男性遗传全男性遗传全男性遗传)male-to-malemale-to-male Y-linked inheritance Single gene disordersSingle gene d
23、isorders1.1.Huntington DiseaseHuntington Disease2.2.Myotonic DystrophyMyotonic Dystrophy3.3.Hereditary Motor Sensory Neuropathy(HMSN)Hereditary Motor Sensory Neuropathy(HMSN)4.4.NeurofibromatosisNeurofibromatosis5.5.Marfan syndromeMarfan syndrome6.6.Cystic FibrosisCystic Fibrosis7.7.Spinal Muscular
24、Atrophy(SMA)Spinal Muscular Atrophy(SMA)8.8.Duchenne Muscular DystrophyDuchenne Muscular Dystrophy9.9.HemophiliaHemophilia如何确定所研究的疾病是单基因病？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：确认方法主要有以下两种：1)参考参考OMIM(Online Mendelian Inheritance in Man)数据库，根据疾病数据库，根据疾病的表型或者临床症状等确定是否属于的表型或者临床症状等确定是否属于OMIM收录的单基因病。收录的单基因病。OMIM除了简
25、略描述各种疾病的临床特征、诊断、鉴别诊断、治疗与预防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。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：网址为：http:/omim.org2)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。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，常用系谱分析系谱
26、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（法来判断某种疾病的遗传方式。系谱图就是从先证者（proband）（家）（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）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、某种遗传病（或性入手，追溯调查其所有家庭成员的数目、亲属关系、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。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单基因病研究举例及进展Rieger 综合征(#MIM 18
27、0500)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：家系家系I I先证者先证者Rieger综合征相关基因和染色体区域PITX2 4q25FOXC1 6p25PAX6 11p13 13q14All these Rieger-syndrome-associated genesencode transcription factors and have be
28、en shown to play important roles in embryonic development测 序 结 果Wild type1-III:4 cloned1-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1
29、00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
30、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，但是使之失去调节基因转录的功能；L54Q位于HD的第1个螺旋，该突变使蛋白质的稳定性丧失；K88E恰改变HD的第50位赖氨酸，不仅使蛋白质丧失功能，并且抑制野生型蛋白正常功能的行使；V45L位于H
31、D的第1个螺旋，该突变仅轻微降低DNA结合活性，而能够大幅上调报告基因的表达。PITX2突变类型与临床表型的关系不同类型的突变在临床表型上存在差异。Kozlowski等针对与不同临床表型相关的5种PITX2突变的功能研究表明，当突变蛋白还拥有部分功能时临床的表型也较轻。Espinoza等的实验也证实没有牙齿异常表型的突变R84W与PITX2调控基因Dlx2启动子的结合能力与野生型相似，而含有所有临床表型的突变T68P则无法调节Dlx2的表达。本研究中本研究中PITX2PITX2基因突变示意图基因突变示意图1 38 98 228 248 271 NCOARHD野生型野生型突变型突变型1 44 8
32、2NCACTT Del突变位于突变位于HDHD的起始部位，移除大段重要功能域，所引起的临床表型，特别是的起始部位，移除大段重要功能域，所引起的临床表型，特别是牙齿的缺失是目前所有报道中最严重的牙齿的缺失是目前所有报道中最严重的.Mutations in 5 regulatory regionSelective Tooth Agenesis(STHAG),is the common generalized term used to describe congenitally missing teeth and is one of the most frequent developmental a
33、nomalies in humans.Genetic linkage studies on non-syndromic hypodontia have so far identified four genes underlying this condition:MSX1,PAX9,WNT10A and AXIN2STHAG3(OMIM#604625)is caused by heterozygous mutation in the PAX9 gene on chr14q12-13,which codes a transcription factor,and essential for the
34、switch in odontogenic potential from the epithelium to the mesenchyme,are expressed in the dental mesenchyme at the initiation stage of tooth developmentA family with HypodontiaPedigree of family DEN29 with haplotypes for a SNP within(rs28933972)and microsatellite markers(D14SA1462,D14S1463,D14S1464
35、)near the PAX9 locus.The shaded haplotype is that segregating with the hypodontia phenotype.A novel g.-1258GA mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia Clin Genet 2011:80:26572Multiple-species comparison of a 60 bp segment bear
36、ing the g.-1258GA variant identified by the arrowRepeat expansion diseasea set of genetic disorders caused by trinucleotide repeat expansion,a kind of mutation where trinucleotide repeats in certain genes exceeding the normal,stable,threshold,which differs per gene.Nature Reviews Genetics 2010 Vol 1
37、1 786-99Huntington Disease(HD)Clinical ClassificationMovement/Cognitive/Psychiatric disorderMean onset age 35-55 years.PrevalenceIncidence 1 in 10,000.Genetic TestingDiagnosticPresymptomatic counselling protocol.Huntington Disease(HD)Physical features:-involuntary movements-weight loss -abnormal gai
38、t -speech&swallowing difficulties.Psychiatric Manifestations:-personality changes-depression -aggression-early onset dementia.Genetic aspects of Huntington diseaseGenetic aspects of Huntington diseaseInheritance ADInheritance ADChromosome locus 4p16.3Chromosome locus 4p16.3Trinucleotide repeat CAG i
39、n 5Trinucleotide repeat CAG in 5 translated region translated regionRepeat sizes Normal 26Repeat sizes Normal 26 Mutable 27-35 Mutable 27-35 Reduced penetrance 36-Reduced penetrance 36-3939 Fully penetrant 40 Fully penetrant 40Protein product HuntingtinProtein product HuntingtinEarly onset form Juve
40、nileEarly onset form Juvenile Paternally transmitted Paternally transmittedDynamic mutations(动态突变动态突变):Mutations in some disorders involve amplification of trinucleotide repeat sequences during gametogenesis.Become mutated through a two-step process.The first mutation,called the premutation,doesnt c
41、ause any clinical symptoms.A second mutation was required to convert the premutation into a full mutation capable of causing the clinical symptoms Structure of the Huntington disease gene.Short vertical bars represent exons.Huntington disease-a triplet repeat diseaseCAG CAG CAG CAG CAG CAG CAG CAG C
42、AG CAG CAG .CAG11-35 CAG triplet repeats are normal:encodes a run of 11-35 glutamine amino acid residues in the protein.A run of 35 glutamine residues causes the protein to aggregate in the brain cells and cause progressive cell death.Runs of 35 CAG repeats in the HD gene expand further(particularly
43、 during male meiosis)causing earlier age of onset in children of men who have the gene anticipation.normal brain HD patient brainMechanisms of expansionMechanism of TNR instability during DNA replication and/or repair processes and the possible roles of DNA repair proteins.DNA repair proteins could
44、either be involved in the formation of slipped-DNAs,the intermediates of TNR instability,or else they could be involved in the processing of these intermediates by mediating correct,escaped,or error-prone repair.Correct repair restores the parental repeat size.Escaped repair involves sealing of the
45、nick resulting in either excess or fewer repeatsrepair proteins may bind to the slipped-DNA preventing repair.Error-prone repair results from incomplete excision of excess repeats leading to a variety of expanded repeat sizes.Mechanisms of pathogenesis for satellite instability disorders.Cont.Mechan
46、isms of pathogenesis for satellite instability disorders.DNA Repair Vol 7(2008)113554The RASopathies:developmental syndromes of Ras/MAPK pathway dysregulationCurrent Opinion in Genetics&Development 2009,19:230236Ras/mitogen-activated protein kinase(MAPK)pathwayPlays an essential role in the control
47、of the cell cycle and differentiationIts dysregulation has profound developmental consequences.Each RASopathies each exhibit unique phenotypic featuresMany share characteristic overlapping features Craniofacial dysmorphologyCardiac malformationsCutaneous,musculoskeletal and ocular abnormalities,Vary
48、ing degrees of neurocognitive impairmentIn some syndromes,an increased risk of developing cancer.Outcomes of mutationsThe vast majority of these mutations result in increased signal transduction down the Ras/MAPK pathwayUsually to a lesser extent than somatic mutations associated with oncogenesis.It
49、 is likely that the strongly activating oncogenic mutations cannot be tolerated as germline mutations.The most common oncogenic BRAF mutation,V600E,does not occur in CFC syndromeThe specific KRAS mutations associated with NS are not the same as the known somatic mutations associated with cancer.Kina
50、sopathy.A clinical phenotype that is caused by germline mutations in the kinase domain of functional proteins that lead to a loss-of-function orgain-of-function of the proteinKinase mutations in human disease:interpreting genotypephenotype relationshipsNature Reviews Genetics 2010 Vol 11 60-74The ch