医学遗传学教学课件：Chapter 12 遗传病的分子和生化基础

Chapter12

遗传病的分子和生化基础

TheMolecularandBiochemicalBasisofGeneticDisease根据蛋白质的普遍性分类

ClassesofProteinsaccordingtotheirgeneralization

管家蛋白Housekeepingproteins

presentinvirtuallyeverycellsandhavefundamentalrolesinmaintenanceofcellstructureandfunction特异性蛋白Specialtyproteins

presentinalimitednumberofcelltypes,haveuniquefunctionsthatcontributetotheindividualityofthecells根据蛋白质的功能分类

ClassesofProteinsaccordingtotheirfunctions酶Enzymes转运和储存Transportandstorage细胞和器官的结构Structureofcellsandorgans维持细胞外稳定Extracellularhomeostasis发育相关基因表达Developmentgeneexpression控制生长和分化Controlofgrowthanddifferentiation细胞内代谢和信息IntercellularmetabolismandcommunicationWewilldiscuss酶缺陷EnzymeDefects

Example:PKU,LysosomalstorageDisease受体蛋白缺陷DefectsinReceptorProteins转运蛋白缺陷TransportDefects结构蛋白缺陷DisordersofStructuralProteins药物遗传疾病PharmacogeneticDiseases遗传性酶病

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苯丙酮尿症Phenylketonuria(PKU)

Phenylketonuria(PKU)Phenylketonuria(PKU)云南一家两个PKU一家两个PKU失察但接受治疗Phenylketonuria(PKU)发病率Incidence:1in16000inpopulation临床表现Clinicalfeatures:Mentalretardation智力障碍

“mousy”odorinurine鼠尿味

seizuredisorder癫痫

hypopigmentation浅染ofskinandhairPhenylketonuria(PKU)遗传学Genetics:Autosomalrecessive(AR)

苯丙氨酸羟化酶（phenylalaninehydroxylasegene，PAH）苯丙氨酸phenylalanine

→酪氨酸tyrosine病理学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，姐姐在国内出生失查，移民到日本后，日本政府为两个孩子的费用全部买单罕见病RareDiseases

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

FromMedline：/medlineplus/rarediseases.html

总发病率：~8.3％

发病率：200,000/300,000,000<

1/1500的为罕见病。平均发病率：25,000,000/7,000*300,000,000=1/120,000ComparisonofNewbornScreeningbetweenChinaandUSABiotinidaseCysticfibrosisgalactosemia(Classical)

Sickle–CdiseaseHearingscreeningCongenitaladrenalhyperplasiaCongenitalhypothyroidism

Sicklecelldiseaseβ-thalassemia5-oxoprolinuria(pyroglutamicaciduria)Glucose6phosphatedehydrogenase

NonketotichyperglycinemiaBenignhyperphenylalaninemia

我国部分地区开展我国部分地区开展我国部分地区开展我国部分地区开展CarbamoylphosphatesynthetaseHyperammonemia/ornithinemia/citrullinemiaProlinemiaEthylmalonicencephalopathyHumanimmunodeficiencyvirus

Toxoplasmosis3-Methylcrotonyl-CoAcarboxylaseCarnitineuptakedefect(Carnitinetransportdefect)Long-chainL-3-hydroxyacyl-CoAdehydrogenasePhenylketonuria/hyperphenylalaninemiaArgininosuccinateacidemiaGlutaricacidemiatype1Medium-chainacyl-CoAdehydrogenasePropionicacidemia(Propionyl-CoAcarboxylase)我国部分地区开展我国部分地区开展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甲基丙二酸血症

Methylmalonicacidemia(MMA)甲基丙二酸血症

Methylmalonicacidemia(MMA)常见的症状：反复呕吐嗜睡惊厥运动障碍智力发育障碍肌张力低下甲基丙二酸血症

Methylmalonicacidemia(MMA)诊断性治疗：维生素B12负荷试验即连续3天肌内注射VitB121mg/d

维生素B12有效型：cblC、cblD、cblF型

cblA、cblB型(部分有效)

维生素B12无效型：mut0、mut-型甲基丙二酸血症

Methylmalonicacidemia(MMA)辅酶钴胺素代谢障碍1.腺苷钴胺素合成缺陷线粒体钴胺素还原酶缺乏(cblA)

线粒体钴胺素腺苷转移酶缺乏(cblB)2.胞浆和溶酶体钴胺素代谢异常引起的腺苷钴胺素和甲基钴胺素合成缺陷(cblC、cblD和cblF)，溶酶体贮积症LysosomalStorageDisease，LSDClathrin-coated溶酶体的功能溶酶体的主要作用是细胞内消化:1、细胞自溶，细胞凋亡

2、细胞免疫，防御作用

3、对某些物质的利用

4、参与分泌过程的调节

5、生殖过程

……ClassificationofLSD糖蛋白Glycoproteinα-mannosidosis,β-mannosidosis,Fucosidosis.Aspartylglucosaminuria脂质和神经鞘脂类lipidandsphingolipid

GMIgangliosidosis,Fabrydisease,Gaucherdisease,Niemann-Pick

diseases粘多糖MucopolysaccharideMucopolysaccharidosis(MPS)

OtherLSDs

Neuronalceroid-lipofuscinoses(NCL),

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

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

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

ofα-galactosidaseA(GLA)

Morethan250kindsofGLADNAmutationsMajorityofthemarepointmutationsAccumulationofglobotriaosylceramide(Gb3)Fabry病的临床表现诊断

家族病史

四肢疼痛

皮肤病变

特有的涡状角膜浊斑

尿道沉渣

组织活检中发现充满脂质的细胞

α－半乳糖苷酶活性检测基因突变分析儿科男性，不明原因的疼痛

儿童期或青春期起病四肢出现间歇性的烧灼样疼痛

感觉异常风湿免疫科疼痛无汗或少汗肾病皮肤科弥漫性体部血管角皮瘤病理科溶酶体内洋葱皮（斑马）样累积物Accumulationofglobotriaosylceramide(Gb3)眼科角膜漩涡状混浊特征性晶状体混浊结膜血管和视网膜血管迂曲

肾脏科在肾透析病人中Fabry病占0.1-1%的心脏科在男性左心室肥大患者中Fabry病占3％在男性晚发型肥大性心肌病患者中Fabry病占6％在女性晚发型肥大性心肌病患者中Fabry病占12％神经内科在18-55岁脑中风病人中Fabry病占3％Am.J.Hum.Genet.2006;79:31-40实际发病率被低估的原因是非典型Fabry病的漏诊Pompedisease糖原累积症缺乏α-glucosidase，溶酶体糖原降解缺陷按照发生的年龄也可分为婴儿型:出生后最初几个月表现为快速进展的全身性肌病及肥厚性心肌病。患儿因心肺衰竭于1岁内死亡少年型:于婴儿晚期及儿童发病,早期症状是走路困难,为进行性肌营养不良,无心脏问题。成人发病型:20～40岁发病。为进行性肢带型肌病。诊断：尿检和酶活性测定婴儿型成人型WewilldiscussEnzymeDefects

DefectsinReceptorProteins

Example:FamilialHypercholesterolemiaTransportDefectsDisordersofStructuralProteinsPharmacogeneticDiseasesFamilialHypercholesterolemia

家族性高胆固醇血症Clinicalfeatures:plasmacholesterolatheromasheartdiseasexanthomasarcuscorneaGene:Low-Density-LipoproteinReceptorGenetics:autosomaldominantMichaelS.BrownJosephL.Goldstein1985WewilldiscussEnzymeDefects

DefectsinReceptorProteinsTransportDefectsExample:CysticFibrosisDisordersofStructuralProteinsPharmacogeneticDiseasesCysticFibrosis囊性纤维化1affected/2500;1carrier/25inCaucasianCFTR,cysticfibrosistransmembraneconductanceregulator囊性纤维化跨膜传导调节蛋白Lifeexpectancyofthe30,000CFpatientsinU.S.A.isunder30years.

Structure&FunctionofCFTRChlorideChannelCysticFibrosisWewilldiscussEnzymeDefects

DefectsinReceptorProteinsTransportDefectsDisordersofStructuralProteinsExample:DMDPharmacogeneticDiseasesDuchenneMuscularDystrophy(DMD)1/3300malebirthsMuscleweaknessat3-5Dieofrespiratoryfailurebefore20SerumcreatinekinaseX-linkreccesiveDMDgene,largestgene,79exonDystrophin1/3acquired,2/3inherited渐冻人：ALS重症肌无力：MG/WewilldiscussEnzymeDefects

DefectsinReceptorProteinsTransportDefectsDisordersofStructuralProteinsPharmacogeneticDiseasesExample:G6PDdeficiency

Pharmacogeneticsdealswiththevariabilityinresponsetodrugsthatisduetogeneticvariation.DietarySelectivepressuresPharmacogeneticswarfarinPathwayPharmacokinetics

Pharmacodynamics

WarfarinDruglabelGlucose-6-phosphatedehydrogenase(G6PD)deficiency

葡萄糖-６-磷酸脱氢酶缺乏症Themostcommondisease-producingenzymedefectofhumanIncidence:10percentofAfrican-AmericanmalesAffect400millionpeopleworld-wide.Genetics:

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

mutationsintheG6PDgene.维持红细胞稳定男性可呈显著酶缺乏。女性杂合子酶活性变异范围大，可接近正常也可显著缺乏。

酶活性20～70%----X染色体随机失活G6PD基因：X连锁不完全显性G6PD变异型分类Ⅰ类：酶活性严重缺乏（活性＜10%）伴有非代偿性慢性溶血特点：无诱因，反复出现慢性溶血Ⅱ类：酶活性中度缺乏（活性＜60%）表现代偿性溶血性贫血特点：在诱因作用下，才诱发急性溶血Ⅲ类：酶活性轻度降低（活性60～100%）特点：表型基本正常可能引起G6PD缺乏者发生溶血的药物类

别药

物氨基喹啉类伯氨喹啉、氯喹、扑疟喹啉、戊氨喹啉砜类氨苯砜、亚磺氨苯砜、噻唑砜磺胺类氨苯磺胺、磺胺醋酰、磺胺异恶唑、柳氮磺胺吡啶、磺胺对甲氧嘧啶硝基呋喃类呋喃妥因、呋喃唑酮、呋喃西林镇痛药乙酰水杨酸、非那西丁、乙酰苯胺其它维生素K（水溶性同类物）、萘、羧苯磺胺、二巯基丙醇、亚甲兰、乙酰苯肼、苯肼、氨甲苯酸、萘啶酸、新砷凡那明、奎宁、奎尼丁、氯霉素PharmacogenomicBiomarkersinDrugLabeling

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