醫(yī)學(xué)遺傳學(xué)教學(xué)課件：Chapter 11 分子病原理-血紅蛋白病

1Chapter11

PrinciplesofMolecularDisease

LessonsfromtheHemoglobinpathies

分子病原理---血紅蛋白病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.

主要由遺傳性或獲得性突變引起的疾病What’smutation?AchangeinbasessequenceororganizationofDNA,usuallyconferringadeleteriouseffect.5萊納斯·卡爾·鮑林

LinusCarlPauling

theoreticalphysicalchemisttwounsharedNobelPrizes1954,chemicalbondandmolecularstructure1962,banthetestingofnuclearweapons.

678JamesWatsonFrancisCrickMauriceWilkinsRosalindElsieFranklin9FromMutationtoDiseaseMutationQualityQuantityProteinDNARNAtRNAmRNADisease10ClassificationofMutationsMutationStaticmutationDynamicmutationPointmutationFragmentmutationFrame-shift

mutationBasesubstitution

Codon

mutationSeeChapter611121314C/TC/TCGA>TGACAA>TAA1516c.780_781insCC，p.R261PfsX69cDNApositioninsertionbasesproteinpositionframeshiftArginineProlineStopcodonposition17Loss-of-FunctionMutation功能喪失Gain-of-FunctionMutation功能增強(qiáng)NovelPropertyMutation新特性MutationsAssociatedwithHeterochronicorEctopicGeneExpression突變導(dǎo)致蛋白質(zhì)在錯(cuò)誤的時(shí)間或錯(cuò)誤的地點(diǎn)表達(dá)基因突變對(duì)蛋白質(zhì)功能的影響

Theeffectofmutationonproteinfunction18血紅蛋白和血紅蛋白病

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）的發(fā)育表達(dá)及

珠蛋白轉(zhuǎn)換（GlobinSwitching）HbA(α2β2)HbF(α2γ2)HbF(α2γ2,<1%)HbA2(α2ε2,<2%)Developmentalgeneexpression(Chapter17)25β珠蛋白的轉(zhuǎn)座子控制區(qū)

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

onproteinfunction27Loss-of-FunctionMutationthegreatmajorityExample:α-thalassemias(α-globingene)?-thalassemias(?-globingene)FunctionLostseverityofdiseaseExample:phenylketonuria(PKU),Chapter12QualityQuantity28Thalassemia地中海貧血

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胎兒水腫2.HbH:--/-α，

α↓,β↑→β4(HbH)precipitationmoderatelyseverehemolyticanemia

較嚴(yán)重的溶血性貧血3.α-thalassemiatrait:--/ααor-α/-α

mildanemia輕度貧血4.Silentcarrier:-α/αα313233Themolecularmechanismof

α-thalassemia1.DeletionFormsMostcommonform（80-85%）

Homologouschromosomemistakepairingandunequalcrossover2.NondeletionFormsα-genemutation34同源染色體錯(cuò)配和不平等交換

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

輸血+去鐵胺Splenectomy脾臟切除hematopoieticstemcelltransplantation

造血肝細(xì)胞移植Hydroxyurea羥基脲→γglobin↑→HbF↑

41Loss-of-FunctionMutationGain-of-FunctionMutationNovelPropertyMutationMutationsAssociatedwithHeterochronicorEctopicGeneExpressionTheeffectofmutation

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

43HemoglobinKempsey（肯普西）44454647Achondroplasia軟骨發(fā)育不全《地鐵里的冒險(xiǎn)》寫到“2011年12月5日，我在車廂中看到了這個(gè)矮小個(gè)頭的男人，他竟是那樣的坦然和自信。車門關(guān)閉后，故事才要上演?！?8AputativemodelforFGFR3signaling4950Loss-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:?-globin--hereditarypersistenceoffetalhemoglobin68細(xì)胞需要足夠的Mecp2關(guān)閉需要關(guān)閉的基因關(guān)閉開(kāi)放Rett綜合征69TheWarbetweenHumanandMalariaGeneWeaponagainstMalaria:

Sicklecelldisease,thalassemia,G6PDdeficiency

70MalariaParasitescouldescapefromimmunesystemandkupffercell7172DarwinWalter

Drawbridge

Crick

waterbeetle73SummaryofChapter11Moleculardisease:Theprimarydisease-causingeventisamutation,eitherinheritedoracquired.Hemoglobinpathies:Globin