医学遗传学教学课件：Chapter 11 分子病原理-血红蛋白病

1Chapter11

PrinciplesofMolecularDisease

LessonsfromtheHemoglobinpathies

分子病原理---血红蛋白病2SampleofTestsThemostcommonformsof

aretheresultofdeletionof

gene.A.α-thalassemia;α–globinB.β-thalassemia;β-globinC.α-thalassemia;β-globinD.β-thalassemia;α–globin3OurlifeismaintainedbymolecularnetworksystemsMolecularnetworksysteminacell(FromExPASyBiochemicalPathways;/cgi-bin/show_thumbnails.pl?2)4Moleculardisease分子病Theprimarydisease-causingeventisamutation,eitherinheritedoracquired.

主要由遗传性或获得性突变引起的疾病What’smutation?AchangeinbasessequenceororganizationofDNA,usuallyconferringadeleteriouseffect.5莱纳斯·卡尔·鲍林

LinusCarlPauling

theoreticalphysicalchemisttwounsharedNobelPrizes1954,chemicalbondandmolecularstructure1962,banthetestingofnuclearweapons.

678JamesWatsonFrancisCrickMauriceWilkinsRosalindElsieFranklin9FromMutationtoDiseaseMutationQualityQuantityProteinDNARNAtRNAmRNADisease10ClassificationofMutationsMutationStaticmutationDynamicmutationPointmutationFragmentmutationFrame-shift

mutationBasesubstitution

Codon

mutationSeeChapter611121314C/TC/TCGA>TGACAA>TAA1516c.780_781insCC，p.R261PfsX69cDNApositioninsertionbasesproteinpositionframeshiftArginineProlineStopcodonposition17Loss-of-FunctionMutation功能丧失Gain-of-FunctionMutation功能增强NovelPropertyMutation新特性MutationsAssociatedwithHeterochronicorEctopicGeneExpression突变导致蛋白质在错误的时间或错误的地点表达基因突变对蛋白质功能的影响

Theeffectofmutationonproteinfunction18血红蛋白和血红蛋白病

HemoglobinsandhemoglobinpathiesMostcommonsingle-genediseases

5%carriersinwholepopulationFirstdeducedprotein

structureFirstcloneddisease-relatedgeneAgoodmodelofgeneactionduringevolutionanddevelopment19StructureandFunctionofHemoglobinFunction:OxygencarrierinredbloodcellsStructure:Foursubunits:α2β2polypeptide多肽+prostheticgroup配基(heme)280,000,000Hb/cell2021F8HisE7His2223HumanHemoglobinGenesStructure24珠蛋白基因（GlobinGenes）的发育表达及

珠蛋白转换（GlobinSwitching）HbA(α2β2)HbF(α2γ2)HbF(α2γ2,<1%)HbA2(α2ε2,<2%)Developmentalgeneexpression(Chapter17)25β珠蛋白的转座子控制区

TheBeta-GlobinLocusControlRegionSuper-enhanceroftranscriptionLCRdeletion---HispanicεγδβThalassemiaLCR26Loss-of-FunctionMutationGain-of-FunctionMutationNovelPropertyMutationMutationsAssociatedwithHeterochronicorEctopicGeneExpressionTheeffectofmutation

onproteinfunction27Loss-of-FunctionMutationthegreatmajorityExample:α-thalassemias(α-globingene)ß-thalassemias(ß-globingene)FunctionLostseverityofdiseaseExample:phenylketonuria(PKU),Chapter12QualityQuantity28Thalassemia地中海贫血

AnImbalanceofGlobin-ChainSynthesisα-globinβ-globinα-thalassemiaα-globinβ-globinβ-globinα-globinNormalβ-thalassemiaExcessglobinprecipitateinthecelldamagemembranedestructRBCanemia29Alpha-Thalassemiasαgenemutationordeletion,β-globinisinrelativeexcess

genotype(――):twoα-geneinsame16chromosomearedeletedgenotype(－α):oneα-geneinone16chromosomeisdeleted30DeletionsoftheAlpha-Globingenes1.HbBart’s:--/--,γ4（HbBart’s）

hydropsfetalis胎儿水肿2.HbH:--/-α，

α↓,β↑→β4(HbH)precipitationmoderatelyseverehemolyticanemia

较严重的溶血性贫血3.α-thalassemiatrait:--/ααor-α/-α

mildanemia轻度贫血4.Silentcarrier:-α/αα313233Themolecularmechanismof

α-thalassemia1.DeletionFormsMostcommonform（80-85%）

Homologouschromosomemistakepairingandunequalcrossover2.NondeletionFormsα-genemutation34同源染色体错配和不平等交换

Homologouschromosomemistakepairingandunequalcrossover35Homologouschromosomemistakepairingandunequalcrossover36TheBeta-Thalassemiasβgenemutationordeletion.α-globinisinrelativeexcess.β0–thalassemiaβ-genemutationordeletionnoβ-globinβ＋-thalassemiaβ-genevariants.insufficientβ-globin3738Theclassic"haironend"appearanceonplainskullradiographsofapatientwithβ-thalassemiamajor39Themolecularmechanismof

β-thalassemia1.Nondeletion

mostcommonform（>90%）

β-genemutation

2.DeletionHomologousmistakeparingandunequalcrossover

40Therapyofβ-thalassemia

Bloodtransfusion+desferrioxamine

输血+去铁胺Splenectomy脾脏切除hematopoieticstemcelltransplantation

造血肝细胞移植Hydroxyurea羟基脲→γglobin↑→HbF↑

41Loss-of-FunctionMutationGain-of-FunctionMutationNovelPropertyMutationMutationsAssociatedwithHeterochronicorEctopicGeneExpressionTheeffectofmutation

onproteinfunction42Gain-of-FunctionMutationQualityorQuantity?1.MutationsthatenhanceonenormalfunctionproteinExample:HemoglobinKempsey2.MutationsthatincreaseproductionofanormalproteinExample:trysomy21(Downsyndrome)

43HemoglobinKempsey（肯普西）44454647Achondroplasia软骨发育不全《地铁里的冒险》写到“2011年12月5日，我在车厢中看到了这个矮小个头的男人，他竟是那样的坦然和自信。车门关闭后，故事才要上演。”48AputativemodelforFGFR3signaling4950Loss-of-FunctionMutationGain-of-FunctionMutationNovelPropertyMutationMutationsAssociatedwithHeterochronicorEctopicGeneExpressionTheeffectofmutation

onproteinfunction51NovelPropertyMutationmutationconferanovelpropertyontheproteinwithoutalteringitsnormalfunctions.Example:Sicklecelldisease525354Glu→Val555657FibresofSickleHemoglobin58FibresofSickleHemoglobin59FibresofSickleHemoglobin–crosssection60616263Sicklecelldisease---therapy64PolyglutamineDiseases

多聚谷氨酸疾病6566Loss-of-FunctionMutationGain-of-FunctionMutationNovelPropertyMutationMutationsAssociatedwithHeterochronicorEctopicGeneExpressionTheeffectofmutation

onproteinfunction67MutationsAssociatedwithHeterochronicorEctopicGeneExpression

Altertheregulatoryregionsofagene

InappropriateexpressionatabnormaltimeorplaceExample1:oncogene--cancer(Chapter16bySong)Example2:ʏ-globin--hereditarypersistenceoffetalhemoglobin68细胞需要足够的Mecp2关闭需要关闭的基因关闭开放Rett综合征69TheWarbetweenHumanandMalariaGeneWeaponagainstMalaria:

Sicklecelldisease,thalassemia,G6PDdeficiency

70MalariaParasitescouldescapefromimmunesystemandkupffercell7172DarwinWalter

Drawbridge

Crick

waterbeetle73SummaryofChapter11Moleculardisease:Theprimarydisease-causingeventisamutation,eitherinheritedoracquired.Hemoglobinpathies:Globin