医学遗传与胚胎发育 Chapter 13 Mitochondrial genetic disorders

Mitochondrial

geneticdisorders

Chapter131KeytopicsStructureofhumanmitochondrialDNA(mtDNA)UniquefeaturesofthegeneticsofmtDNAMutationsinmtDNAandDiseases(LHON,MELAS)2Mitochondrial1857,Mitowasdiscoveredincytoplasmofanimal;1898,NamedbyCarlBenda;1963,NassfoundmtDNAinchickenoocyte;1981,AndersonpublishedfullsequenceofhumanmtDNA;1987,WallaceprovedthatmtDNAmutationstriggerLeberhereditaryopticneuropathy

.CarlBenda(1857–1932)31.StructureofhumanmitochondrialDNANo.25chromosomeorMchromosomeDoublestrand(closedring)

Heavystrand;Lightstrand

16569bp,encodes37genes

13genesencodingproteinsinvolvedrespiratorychain22genesencodingtRNA2genesencodingrRNANointronOnecellhashundredsofmitochondrionwhichwith2~10copiesofmtDNA42.1Semi–autonomousreplication

(半自主复制)

TranscriptionofmitochondrialDNA(mtDNA)takesplaceinthemitochondrion,independentlyofthenucleus.Butitisstillcontrolledbynucleargenes.

2.2Specialcodon（特殊密码子）

UGA（Trp）

tRNAdegeneracy，22tRNAidentify48codons

2.UniquefeaturesofthegeneticsofmtDNA5Reflectsthefactthatspermmitochondriaaregenerallyeliminatedfromtheembryo,sothatmtDNAisalmostalwaysinheritedentirelyfromthemother.MalesinherittheirmtDNAfromtheirmothers.Theydonotpassittotheiroffspring.2.3Thematernalinheritance

(母系遗传)6

Withinthematurityoftheoocyte,theamountofmitochondriadecreasedrapidly,from100,000tolessthan100,thisis“geneticbottleneck”.Itcandecreasetheprobabilityofdisease-carryingmothertotransmitthemutantgenetotheiroffspring.Mitochondrialgeneticbottleneck(遗传瓶颈)OocyteMatureoocyteEarlydevelopment100000mt10~100mt100000mt

7Homoplasmy(纯质)

：AsinglecellortissueharborssamemoleculesthathaveanmtDNAmutationorwildtype.Heteroplasmy(杂质)

：AsinglecellortissueharborssomemoleculesthathaveanmtDNAmutationandothermoleculesthatdonot.ThisheterogeneityinDNAcomposition,termedheteroplasmy,isanimportantcauseofvariableexpressioninmitochondrialdiseases.8Atcelldivision,themultiplecopiesofmtDNAineachofthemitochondriainacellreplicateandsortrandomlyamongnewlysynthesizedmitochondria.Themitochondria,inturn,aredistributedrandomlybetweenthetwodaughtercells.2.4Replicativesegregation（复制分离）922.5Quantitativethreshold(阈值效应)10ConceptofquantitativethresholdThemutantmtDNAinheteroplasmywillonlyleadtoonsetofthediseasewhenitsignificantlywithaquantitativethreshold.TheseverityofthediseaseassociatedwithamtDNAmutationwilldependontherelativeproportionofnormalandmutantmtDNAinthecellsofaparticulartissue.Femalesheteroplasmonwithoutclinicalfeaturescanbeasymptomaticcarrierstotrasmitthemutationtoalloftheirchildren.

112.6HighmutationfrequencyThemutationrateofmtDNAisabout10timeshigherthanthatofnuclearDNA.CausedbyalackofDNArepairmechanismsinthemtDNAandpossiblyalsobydamagefromfreeoxygenradicalsreleasedduringtheoxidativephosphorylationprocess.UnlikenuclearDNA,mtDNAcontainsnointrons.NoDNAbindingprotein.

121.Replication:Semi-autonomous

2.SpecialCodon:UGA（Trp）3.Maternalinheritance:Geneticbottleneck4.Replicativesegregation:mtDNAandmitochondriondistributerandomlybetweenthetwodaughtercells

5.Quantitativethreshold:Homoplasmyandheteroplasmy

6.Highmutationfrequency:

10timeshigherUniquefeaturesofthegeneticsofmtDNA13EachtissuetyperequiresacertainamountofmitochondriallyproducedATPfornormalfunction.AlthoughsomevariationinATPlevelsmaybetolerated,thereistypicallyathresholdlevelbelowwhichcellsbegintodegenerateanddie.OrgansystemswithlargeATPrequirementsandhighthresholdstendtobetheonesmostseriouslyaffectedbymitochondrialdiseases.(Thecentralnervoussystemconsumesabout20%ofthebody'sATPproduction)Morethan100differentrearrangementsand100differentpointmutationshavebeenidentifiedinmtDNAthatcancauseabout60kindsofhumandisease,ofteninvolvingthecentralnervousandmusculoskeletalsystems.3.MutationsinmtDNAandDisease14HighATPrequirementstissues眼外肌麻痹θ上睑下垂白内障色素性视网膜病视神经萎缩脑病复发性休克癫痫和痴呆精神病和抑郁症共济失调偏头痛肥大性心肌病扩张性心肌病心传导阻滞预激综合征153.1Leberhereditaryopticneuropathy(LHON,Leber遗传性视神经病)3.1.1Majorclinicfeatures:Rapidlossofvisioninthecentralvisualfieldasaresultofopticnervedeath;Visionlosstypicallybeginsinthethirddecadeoflifeandisusuallyirreversible;

Moremalesthanfemales(6M:1F)areaffected.MutationsinmtDNAandDisease16Leberhereditaryopticneuropathy3.1.2NineMitogenedisordersareinvolvedin(ND1,ND2,CO1,ATP6,CO3,ND4,ND5,ND6,CYTB)3.1.3LHONisheterogeneous,itcanbecausedbydifferentmutations,90%harbor:

MTND1*LHON3460A

MTND4*LHON11778A，50-75%MTND6*LHON14484C.3.1.4Homoplasmic.

Heteroplasmic.

Threshold≥70%173.2Mitochondrialencephalomyopathy,lacticacidosis,andstroke-likeepisodes(MELAS,)

线粒体脑肌病伴乳酸酸中毒及中风样发作综合征

3.2.1Majorclinicfeatures：Stroke-likeepisodes（复发性休克，卒中样发作）Encephalomyopathy（脑肌病，肌阵挛，共济失调）Dementia（痴呆）Sensorineuralhearingloss（感觉神经性听觉丧失）Lacticacidosis（丙酮酸代谢障碍乳酸酸累积中毒）Note:encephalomyopathy['ensefələmaɪ'əpəθɪ]18Mitochondrialencephalomyopathy,lacticacidosis,andstroke-likeepisodes(MELAS)

3.2.2MutationoftRNAleu/ValgenecausesMELAS;3.2.3MELASisheterogeneous,itcanbecausedbydifferentmutations:

MTTL1*MELAS3243A→GMTTV*MELAS3252/3271/3291;MTCO33.2.4Heteroplasmic（MTTL1*MELAS3243A→G）

Mutaion≥90%:

Stroke-likeepisodes,encephalomyopathy,dementia

Mutaion40%-50%:extrernalophthalmoplegia（眼外肌麻痹）,myopathy,deafness

Variableclinicfeaturesindifferentmutationsites.Note:Ophthalmoplegia[ɒfˌθælmə'pli:dʒɪr]19MutationsinmtDNAandDiseasePointmutation

Missensemutationsinoxidativephosphorylationprotein

pointmutationsintRNAorrRNAgenes

Rearrangement

Deletionandinsertion

CopynumbermutationMuchlowerthannormal20Characteristicsofmitochondrialdisorders1.Maternalinheritance2.Quantitativethreshold3.TissuesspecificityThecentralnervousandmusculoskeletalsystemsareoftenaffected.4.P