遺傳匯總第六組地中海貧血tay-sachs disease

Tay-SachsDisease演講：蔣潤李玥成員：鐘京諭丁飛雪岑卿卿潘思遠仇嘉宇

張文青王宇婷任佳寧夏倩StoryI-3LivinginaPsychiatricHomeII-1DiedofTay-SschsDiseaseIntroductionName:

AmauroticIdiocy/LysopspmalstoragediseasePathology:

HEXAMutationCategory:

AutosomalRecessiveHistory:

1881Tay/1896Sachs1.PhenotypicFeatureMutationseverity→phenotypeseverityNeurodegenerationRetinalCherry-redSpot(Infantile-onset)Psychosis（adult-onset）FeaturesConcept1GeneticDriftRandomsamplingIndeterminingwhetheranallelesurvivesordisappearsReducegeneticvariationAparticularformFeatures2.GeneticFeatureConcept2

FounderEffectAverysmallpopulationLossofgeneticvariationBedifferentbothgenotypicallyandphenotypicallyFeaturesEthnicVariation 1in360000non-AshkenaziJewish 1in3600AshkenaziJewishMendel'sLawofInheritanceFeaturesPathogenesis

神經(jīng)節(jié)苷脂（ganglioside）沉積病Chemicalnature:glycosylsphingolipid(鞘糖脂)Structure:(pic.)Location:neuronalmembranes---dendrites,axonterminiFunctions:receptorforglycoproteinhormonesbacterialtoxins(pic.)Synthesis:ERplexlysosome(GM2modifiedbyHEXA)Commongangliosides:GM1,GM2,GM3;GD1a,GD1b;D2,GD3GangliosideinvitroStructureofGM2CutbyHEXAHexosaminidaseA(

HEXA)

己糖氨酶Structure

α/βheterodimeralphapolypeptideGene

αsubunit---HEXAgene---chromosome15---15q23-q24

βsubunit---HEXBgene---chromosome5Cofactor:

GM2activatorprotein(GM2A)HowdoescofactorGM2Awork?PathologicalMechanismGenemutation

1.MutationsinHEXAgene→Tay-Sachsdisease

GM2AgeneHEXAgeneHEXBgene>100

differentmutationsdiscovered(ininfantilecasesalone)mostcommonmutation（in>80%patients):4basepairaddition(TATC)exon11(HEXAgene)earlystopcodonHexAdeficiencyinαsubunit

TheaccumulationofGM2inlysosomesGM2gangliosideproducestoxicbyproducts

NeuronaldeathGM2AgeneHEXAgeneHEXBgene3.MutationsinGM2Agene

SamephenotypeasTay-SachsDiseaseGenocopy擬基因型

2.MutationsinHEXBgene

SimilarphenotypeasTay-SachsDiseaseSandhoffdiseaseSubstrateReductionTherapyWhatisitCurrentStatusZavesca?intrials(forGaucherdisease---G.C(葡萄糖腦苷脂)storageinlysosome）

Treatment

2.GeneTherapyWhatisit：AAVs（virus）

→braincell（chromosome19）CurrentStatus：SuccessinmicetrialChallenges：creatingeffectivevectorsoverex