醫(yī)學遺傳學教學課件：Chapter 12 遺傳病的分子和生化基礎

Chapter12

遺傳病的分子和生化基礎

TheMolecularandBiochemicalBasisofGeneticDisease根據蛋白質的普遍性分類

ClassesofProteinsaccordingtotheirgeneralization

管家蛋白Housekeepingproteins

presentinvirtuallyeverycellsandhavefundamentalrolesinmaintenanceofcellstructureandfunction特異性蛋白Specialtyproteins

presentinalimitednumberofcelltypes,haveuniquefunctionsthatcontributetotheindividualityofthecells根據蛋白質的功能分類

ClassesofProteinsaccordingtotheirfunctions酶Enzymes轉運和儲存Transportandstorage細胞和器官的結構Structureofcellsandorgans維持細胞外穩(wěn)定Extracellularhomeostasis發(fā)育相關基因表達Developmentgeneexpression控制生長和分化Controlofgrowthanddifferentiation細胞內代謝和信息IntercellularmetabolismandcommunicationWewilldiscuss酶缺陷EnzymeDefects

Example:PKU,LysosomalstorageDisease受體蛋白缺陷DefectsinReceptorProteins轉運蛋白缺陷TransportDefects結構蛋白缺陷DisordersofStructuralProteins藥物遺傳疾病PharmacogeneticDiseases遺傳性酶病

HereditaryEnzymopathyTheinbornerrorsofmetabolismiscausedbygenemutationwhichleadtoenzymeproteinvariants.SubstrateProductP’S’S’’P’’MutantEnzymeExamplesofHereditaryEnzymopathy疾病PhenylketonuriaLesch-NyhansyndromeTay-SachsDiseaseMucopolysaccharidoses

?Huntersyndrome

?Hurler/Scheiesyndrome

?SanfilipposyndromeI-cellDiseaseHomocystinuria主要致病基因PAH,PhenylalaninehydroxylaseHprt,HypoxanthineguaninephosphoribosyltransferaseHexA,HexosaminidaseA?iduronate-2-sulphatase?α-L-iduronidase?α-D-N-AcetylglucosaminidaseN-acetylglucosaminyl-1-phosphotransferaseCystathioninesynthase苯丙酮尿癥Phenylketonuria(PKU)

Phenylketonuria(PKU)Phenylketonuria(PKU)云南一家兩個PKU一家兩個PKU失察但接受治療Phenylketonuria(PKU)發(fā)病率Incidence:1in16000inpopulation臨床表現Clinicalfeatures:Mentalretardation智力障礙

“mousy”odorinurine鼠尿味

seizuredisorder癲癇

hypopigmentation淺染ofskinandhairPhenylketonuria(PKU)遺傳學Genetics:Autosomalrecessive(AR)

苯丙氨酸羥化酶（phenylalaninehydroxylasegene，PAH）苯丙氨酸phenylalanine

→酪氨酸t(yī)yrosine病理學Pathology:Phenylalanineanditsderivatives（衍生物）

damagethedevelopingbrainPhenylketonuria(PKU)PAHPhenylketonuria(PKU)phenylalaninetyrosineP’S’S’’P’’PAHMentalretardation

“mousy”odorinurineseizuredisorderhypopigmentationofskinandhairBH4缺乏型PKUTherapy:DietaryreductionofphenylalanineNewbornscreeningNewbornScreeningNewbornScreeningNewbornScreeningNewbornScreening

姐弟都是PKU，姐姐在國內出生失查，移民到日本后，日本政府為兩個孩子的費用全部買單罕見病RareDiseases

“Adiseaseisrareiffewerthan200,000peopleintheUnitedStateshaveit.Therearecloseto7,000rarediseasesandabout25millionpeopleintheU.S.haveone.Manyrarediseasesarecausedbychangesingenesandarecalledgeneticdiseases.”

FromMedline：/medlineplus/rarediseases.html

總發(fā)病率：~8.3％

發(fā)病率：200,000/300,000,000<

1/1500的為罕見病。平均發(fā)病率：25,000,000/7,000*300,000,000=1/120,000ComparisonofNewbornScreeningbetweenChinaandUSABiotinidaseCysticfibrosisgalactosemia(Classical)

Sickle–CdiseaseHearingscreeningCongenitaladrenalhyperplasiaCongenitalhypothyroidism

Sicklecelldiseaseβ-thalassemia5-oxoprolinuria(pyroglutamicaciduria)Glucose6phosphatedehydrogenase

NonketotichyperglycinemiaBenignhyperphenylalaninemia

我國部分地區(qū)開展我國部分地區(qū)開展我國部分地區(qū)開展我國部分地區(qū)開展CarbamoylphosphatesynthetaseHyperammonemia/ornithinemia/citrullinemiaProlinemiaEthylmalonicencephalopathyHumanimmunodeficiencyvirus

Toxoplasmosis3-Methylcrotonyl-CoAcarboxylaseCarnitineuptakedefect(Carnitinetransportdefect)Long-chainL-3-hydroxyacyl-CoAdehydrogenasePhenylketonuria/hyperphenylalaninemiaArgininosuccinateacidemiaGlutaricacidemiatype1Medium-chainacyl-CoAdehydrogenasePropionicacidemia(Propionyl-CoAcarboxylase)我國部分地區(qū)開展我國部分地區(qū)開展ComparisonofNewbornScreeningbetweenChinaandUSAComparisonofNewbornScreeningbetweenChinaandUSABetaketothiolase(mitochondrialacetoacetyl-CoAthiolase)Homocystinuria(cystathioninebetasynthase)Multiplecarboxylase(Holocarboxylasesynthetase)TrifunctionalproteindeficiencyMethylmalonicacademia(VitaminB12Disorders)3-Hydroxy3–methylglutaricaciduriaMaplesyrupurinediseaseTyrosinemiaType1CitrullinemiatypeI(Argininosuccinatesynthetase)Isovalericacidemia(Isovaleryl-CoAdehydrogenase)MethylmalonicAcidemia(methylmalonyl-CoAmutase)Verylong-chainacyl-CoAdehydrogenaseComparisonofNewbornScreeningbetweenChinaandUSA2-Methyl-3-hydroxybutyricaciduriaCarnitineacylcarnitinetranslocaseGlutaricacademiaTypeIIMalonicacademia(Malonyl-CoAdecarboxylase)2-Methylbutyryl-CoAdehydrogenaseMethylmalonicacidemia(CblC,D)GalactoseepimeraseMedium-chainketoacyl-CoAthiolase3-MethylglutaconicaciduriaCitrullinemiatypeIIGalactokinaseHypermethioninemiaArginemia(Arginasedeficiency)ComparisonofNewbornScreeningbetweenChinaandUSACarnitinepalmitoyltransferaseIShort-chainacyl-CoAdehydrogenaseDefectsofbiopterincofactorbiosynthesisCarnitinepalmitoyltransferaseIIIsobutyryl-CoAdehydrogenaseTyrosinemiatypeIIDefectsofbiopterincofactorregenerationDienoyl-CoAreductaseMedium/ShortchainL-3-hydroxyacyl-CoAdehydrogenaseTyrosinemiatypeIII甲基丙二酸血癥

Methylmalonicacidemia(MMA)甲基丙二酸血癥

Methylmalonicacidemia(MMA)常見的癥狀：反復嘔吐嗜睡驚厥運動障礙智力發(fā)育障礙肌張力低下甲基丙二酸血癥

Methylmalonicacidemia(MMA)診斷性治療：維生素B12負荷試驗即連續(xù)3天肌內注射VitB121mg/d

維生素B12有效型：cblC、cblD、cblF型

cblA、cblB型(部分有效)

維生素B12無效型：mut0、mut-型甲基丙二酸血癥

Methylmalonicacidemia(MMA)輔酶鈷胺素代謝障礙1.腺苷鈷胺素合成缺陷線粒體鈷胺素還原酶缺乏(cblA)

線粒體鈷胺素腺苷轉移酶缺乏(cblB)2.胞漿和溶酶體鈷胺素代謝異常引起的腺苷鈷胺素和甲基鈷胺素合成缺陷(cblC、cblD和cblF)，溶酶體貯積癥LysosomalStorageDisease，LSDClathrin-coated溶酶體的功能溶酶體的主要作用是細胞內消化:1、細胞自溶，細胞凋亡

2、細胞免疫，防御作用

3、對某些物質的利用

4、參與分泌過程的調節(jié)

5、生殖過程

……ClassificationofLSD糖蛋白Glycoproteinα-mannosidosis,β-mannosidosis,Fucosidosis.Aspartylglucosaminuria脂質和神經鞘脂類lipidandsphingolipid

GMIgangliosidosis,Fabrydisease,Gaucherdisease,Niemann-Pick

diseases粘多糖MucopolysaccharideMucopolysaccharidosis(MPS)

OtherLSDs

Neuronalceroid-lipofuscinoses(NCL),

GlycogenStoragediseasetypeII(Pompe)GaucherdiseaseGaucherdiseasewasfirstdescribedin1882byFrenchphysicianPhilippeCharlesErnestGaucherafterheevaluatedthecorpseofa32-year-oldwomanwithanenlargedspleen(oneofthedisorder’sdistinguishingsigns).Glucocerebrosidase(?

-Glu)deficiency1/40000-60000？GauchercellsLipid-engorgedcellswitheccentricnuclei,knownasGauchercells,accumulateanddisplacehealthynormalcellsinbonemarrowandvisceralorgansskeletaldeteriorationanemiahepatosplenomegalyaffectthebrainandnervoussystemTherapyofGaucherdisease

---EnzymeReplacementTherapy(ERT)FabryDiseaseAnderson-FabryDiseaseDrJohannesFabryDrWilliamAndersonFabryDisease法布雷病X-linkedLysosomalStorageDisorderDeficiency

ofα-galactosidaseA(GLA)

Morethan250kindsofGLADNAmutationsMajorityofthemarepointmutationsAccumulationofglobotriaosylceramide(Gb3)Fabry病的臨床表現診斷

家族病史

四肢疼痛

皮膚病變

特有的渦狀角膜濁斑

尿道沉渣

組織活檢中發(fā)現充滿脂質的細胞

α－半乳糖苷酶活性檢測基因突變分析兒科男性，不明原因的疼痛

兒童期或青春期起病四肢出現間歇性的燒灼樣疼痛

感覺異常風濕免疫科疼痛無汗或少汗腎病皮膚科彌漫性體部血管角皮瘤病理科溶酶體內洋蔥皮（斑馬）樣累積物Accumulationofglobotriaosylceramide(Gb3)眼科角膜漩渦狀混濁特征性晶狀體混濁結膜血管和視網膜血管迂曲

腎臟科在腎透析病人中Fabry病占0.1-1%的心臟科在男性左心室肥大患者中Fabry病占3％在男性晚發(fā)型肥大性心肌病患者中Fabry病占6％在女性晚發(fā)型肥大性心肌病患者中Fabry病占12％神經內科在18-55歲腦中風病人中Fabry病占3％Am.J.Hum.Genet.2006;79:31-40實際發(fā)病率被低估的原因是非典型Fabry病的漏診Pompedisease糖原累積癥缺乏α-glucosidase，溶酶體糖原降解缺陷按照發(fā)生的年齡也可分為嬰兒型:出生后最初幾個月表現為快速進展的全身性肌病及肥厚性心肌病?；純阂蛐姆嗡ソ哂?歲內死亡少年型:于嬰兒晚期及兒童發(fā)病,早期癥狀是走路困難,為進行性肌營養(yǎng)不良,無心臟問題。成人發(fā)病型:20～40歲發(fā)病。為進行性肢帶型肌病。診斷：尿檢和酶活性測定嬰兒型成人型WewilldiscussEnzymeDefects

DefectsinReceptorProteins

Example:FamilialHypercholesterolemiaTransportDefectsDisordersofStructuralProteinsPharmacogeneticDiseasesFamilialHypercholesterolemia

家族性高膽固醇血癥Clinicalfeatures:plasmacholesterolatheromasheartdiseasexanthomasarcuscorneaGene:Low-Density-LipoproteinReceptorGenetics:autosomaldominantMichaelS.BrownJosephL.Goldstein1985WewilldiscussEnzymeDefects

DefectsinReceptorProteinsTransportDefectsExample:CysticFibrosisDisordersofStructuralProteinsPharmacogeneticDiseasesCysticFibrosis囊性纖維化1affected/2500;1carrier/25inCaucasianCFTR,cysticfibrosistransmembraneconductanceregulator囊性纖維化跨膜傳導調節(jié)蛋白Lifeexpectancyofthe30,000CFpatientsinU.S.A.isunder30years.

Structure&FunctionofCFTRChlorideChannelCysticFibrosisWewilldiscussEnzymeDefects

DefectsinReceptorProteinsTransportDefectsDisordersofStructuralProteinsExample:DMDPharmacogeneticDiseasesDuchenneMuscularDystrophy(DMD)1/3300malebirthsMuscleweaknessat3-5Dieofrespiratoryfailurebefore20SerumcreatinekinaseX-linkreccesiveDMDgene,largestgene,79exonDystrophin1/3acquired,2/3inherited漸凍人：ALS重癥肌無力：MG/WewilldiscussEnzymeDefects

DefectsinReceptorProteinsTransportDefectsDisordersofStructuralProteinsPharmacogeneticDiseasesExample:G6PDdeficiency

Pharmacogeneticsdealswiththevariabilityinresponsetodrugsthatisduetogeneticvariation.DietarySelectivepressuresPharmacogeneticswarfarinPathwayPharmacokinetics

Pharmacodynamics

WarfarinDruglabelGlucose-6-phosphatedehydrogenase(G6PD)deficiency

葡萄糖-６-磷酸脫氫酶缺乏癥Themostcommondisease-producingenzymedefectofhumanIncidence:10percentofAfrican-AmericanmalesAffect400millionpeopleworld-wide.Genetics:

X-linkeddominante(XD),incompletedominantegenelocationXq28,13Basicdefect:

mutationsintheG6PDgene.維持紅細胞穩(wěn)定男性可呈顯著酶缺乏。女性雜合子酶活性變異范圍大，可接近正常也可顯著缺乏。

酶活性20～70%----X染色體隨機失活G6PD基因：X連鎖不完全顯性G6PD變異型分類Ⅰ類：酶活性嚴重缺乏（活性＜10%）伴有非代償性慢性溶血特點：無誘因，反復出現慢性溶血Ⅱ類：酶活性中度缺乏（活性＜60%）表現代償性溶血性貧血特點：在誘因作用下，才誘發(fā)急性溶血Ⅲ類：酶活性輕度降低（活性60～100%）特點：表型基本正?？赡芤餑6PD缺乏者發(fā)生溶血的藥物類

別藥

物氨基喹啉類伯氨喹啉、氯喹、撲瘧喹啉、戊氨喹啉砜類氨苯砜、亞磺氨苯砜、噻唑砜磺胺類氨苯磺胺、磺胺醋酰、磺胺異惡唑、柳氮磺胺吡啶、磺胺對甲氧嘧啶硝基呋喃類呋喃妥因、呋喃唑酮、呋喃西林鎮(zhèn)痛藥乙酰水楊酸、非那西丁、乙酰苯胺其它維生素K（水溶性同類物）、萘、羧苯磺胺、二巰基丙醇、亞甲蘭、乙酰苯肼、苯肼、氨甲苯酸、萘啶酸、新砷凡那明、奎寧、奎尼丁、氯霉素PharmacogenomicBiomarkersinDrugLabeling

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