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PrinciplesofMolecularDisease
Gene
Thebasichereditaryunit,aDNAsequence
requiredforproductionofafunctionalproduct,usuallyaprotein,butrarely,anuntranslatedRNA.
Genemutation
Achange
inbasessequenceororganizationof
DNA,usuallyconferringadeleteriouseffect.
BasesubstitutionPointmutationCodonmutation
StaticmutationFrame-shiftMutationmutationFragmentmutationDynamicmutation
Pointmutation
AchangeinoneorfewbasesofDNA,includingbasesubstitution,Codonmutationandframe-shiftmutation.
samesensemutation(silent)
non-sensemutation
1.Basesubstitution
missensemutation
terminatorcodonmutation
2.
Codonmutation
3.Frame-shiftmutation
deletion
insertion
Fragmentmutation
inversion
duplication
fusiongeneDynamicmutation
Unstabletrinucleotiderepeatamplification,E.g.FragileXsyndrome(CGG)>200,Huntington’sDisease(CAG)>35.
harmfulness
Consequenceofgenemutation
neutrality
advantage
Theeffectofmutationonproteinfunction
Disease-causingmutation
1.loss-of-FunctionMutationα-thalassemiapku
2.Gain-of-FunctionMutation
EnhanceoneNormalFunctionofaprotein
hemoglobinKempsey
IncreaseproductionofaNormalproteintrisomy21
3.NovelpropertyMutation
sicklecelldisease
4.MutationAssociatedwithHeterochronicorEctopicGeneExpression
r-globingene→adult
oncogene→cancer
Moleculardisease
Thediseasesiscausedbygenemutationwhichleadtoproteinvariants.
HemoglobinsandHemoglobinopathies
WHO:world’spopulation
>5%carriersofgenesforclinicallyimportantdisordersofhemoglobin
HumanHemoglobinsandTheGenesHumanHemoglobins
twoαchains.141aa(ζ)
FourSubunits
twoβchains.146aa(ε.γ.δ)
Eachsubunits:aglobinchainandaheme.
HemoglobinGenesGenecluster
1.αandα-likegenescluster5’→ζ→Ψζ→Ψα1→α2→α1→3
’
16p13.1-p13.3,2n→4α
1313299100141
1
2
1
5‘3’16pter-p13.32.βandβ-likegenescluster
5’→ε→Gγ→Aγ→Ψβ→δ→β→3’
11p15.5,2n→2β
11p15.513031104105146
εG
A
ψ
δβ5’3’
Pseudogene
Thegenesaresimilartothenormalgene,butwithoutnormalgenefunction.
e.gΨζ,Ψα,ΨβDevelopmentalExpressionofGlobingene
Transcription→modification→Translation→modification→Assembly
1.tissuepropertyRegulation2.timeproperty3.amounts(Dosage)balance
1.Structuralvariants(Abnormalhemoglobin)>800
Hemoglobinopathies
2.Thalassemias(amountsimbalance)>400
3.Hereditarypersistenceoffetalhemoglobin
Abnormalhemoglobin
Sicklecellanemia(OMIM#603903)
Sicklecellhemoglobin(HbS)
1949PaulingThefirstabnormalhemoglobintobedetected
Itisduetoasinglenucleotidesubstitutionthatchangesthecodonofthesixthaminoacidofβglobinfromglutamicacidtovaline
(GAGGTG:Glu6val).
SicklecellanemiaClinicalfeatures
HbSHbS:Homozygotes→sicklecellAnemia.HbAHbS:Heterozygotes→sicklecelltraitinlowoxygenpressureIncidence
About1in600AfricanAmericansGeographicdistribution
MostfrequentlyinequatorialAfricaWorldwide
GeographicdistributionGenetics
Autosomalrecessive(AR),genelocation11P15.5Basicdefect
βgene
β6GAG→GTG
βmRNA
β6GAG→GUG
βglobin
β6glu→Val
HbS(α2β6Val2)(α2βs2)
Pathology
The
mutation(GAGGTG:Glu6val)
inβglobindecreasesthesolubilityofdeoxygenatedhemoglobinandcauseittoformagelatinousnetworkoffibrouspolymers.Thus,erythrocytesbecomefirmanddeformintosickle-shapedcells.
Sicklecellsareunabletopassthroughsmallarteriesandcapillaries.Thesebecome
clogged
andcauselocaloxygendeficiency
inthetissues.
Defectiveerythrocytesaredestroyed(hemolysis).Chronicanemiaanditsnumeroussequelaesuchasheartfailure,liverdamage,andinfectionaretheresult.
sicklecellsnormalcells粘滞性僵硬Prenataldiagnosis
possiblewithDNAtechniques.
Treatment
MolecularBasisofAbnormalhemoglobin
1.Missensemutation:
HbS(β6glu→val)
2.Non-sensemutation:
HbMckees-Rock
(β145UAU→UAA)
3.Terminationcodonmutation:
Hbconstantspring
(α142UAA→CAA)
4.Frame-shiftmutation:
Hbwayne
(α138UCC↑)
5.Codonmutation:
HbGumHiu
(β91-95↑)
6.Fusiongene:
Hblepore
(δβ)
Hbanti-lepore(βδ)
Thalassemia
AnImbalanceofGlobin-Chainsynthesis
Themutationsreducethesynthesisorstabilityofeithertheα-orβ-globinchain,tocauseα-orβ-thalassemia,respectively.
Theimbalanceintheratioofα:βchain→theexcessnormalchainsprecipitateinthecell→damagingthemembraneandleadingtoredbloodcelldestruction→anemia
FirstdiscoveredinpersonofMediterraneanorigin
Widedistributeintheworld
MediterraneanMiddleEastPortsofAfricaIndiaandAsiaDistributeintheworld
Alpha-Thalassemias
αgenemutationordeletion,β-globinisinrelativeexcess
α0(α1)Thalassemias
genotype(――)twoα-geneinsame16chromosomearedeletion
α+(α2)Thalassemias
genotype(-α)oneα-geneinone16chromosomeisdeletion
DeletionsoftheAlpha-Globingenes
1.HbBart’s
――/――,Υ4(HbBart’s)hydropsfetalis
2.HbH
――/-α,ααT/――orααCS/――
α↓,β↑→β4(HbH)precipitation
moderatelyseverehemolyticanemia
3.Alpha-thalassemiatrait
――/ααor-α/-α
mildanemia
4.Silentcarrier
―α/αα
Themolecularmechanismofα-thalassemia
1.DeletionForms
Homologouschromosomemistakepairingandunequal
crossover
Mostcommonform
2.NondeletionForms
α-gene
mutation
less
Beta-Thalassemias
βgenemutationordeletion,α-globinisinrelativeexcess
β0–thalassemiaβ-genemutationordeletion,noβ-globin
β+
-thalassemiaβ-genevariants,Someβ-globin
1.β-thalassemiamajor
Mostpatientswithoutnormalβ-thalassemiaalleles.
Severeanemia
needforlifelongmedicalmanagement.
β0/β0、β0/β+、β0/δβ0、δβ0/δβ0
2.β-thalassemiaminor
patientshavehypochromic,microcyticredbloodcell,slightanemia
β+/βA、β0/βAorδβ0/δβA,
HbA2(α2δ2)↑orHbF(α2γ2)↑
3.Hereditarypersistenceoffetalhemoglobin
highlevelthepersistenceofr-globingeneexpressionthroughoutadultlife
δ.β↓,r↑→HbF(α2γ2)
TheMolecularBasisofBeta-thalassemia
1.Nondeletion
β-genemutation
most
commonform
2.Deletion
Homologousmistakeparingandunequalcrossover
less
Mutationsite:
1.Codingsequencesinβ-gene→β02.5’-regulationsequencesinβgene→β0orβ+
3.splicejunctionsequencesinβ-gene→β04.5’-cappingsequencesinβ-gene→β+
5.3’-tailingsequencesinβ-gene→β+
Master:
GeneandGenemutationMoleculardiseaseHemoglobinopathiesAbnormalhemoglobin,SicklecellanemiaMolecularBasisofAbnormalhemoglobinThalassemiaAlpha-Thalassemias,Beta-Thalassemias
Understand:ConsequenceofgenemutationTheeffectofmutationonproteinfunctionHumanHemoglobinsandTheirGenesThemolecularmechanismofα-thalassemiaThemolecularmechanismofβ-thalassemia
TheMolecularandBiochemicalBasisofGeneticDiseases
TaoZhangDepartmentofMedicalGeneticsHealthScienceCenterPekingUniversity
EnzymedefectsandDiseases
Hereditaryenzymopathy(Enzymopathy)
Theinbornerrorsofmetabolismiscausedby
genemutationwhichleadtoenzymeproteinvariants200+(AR)
metabolismS1E12S2E23S3E3PPS4S5
Gene G1 G2
G3
(mutation)
Enzyme EAB EBC
ECD(defect)
MetabolismA B C∥DPathologyerrorsofmetabolism
ThemechanismofHereditaryenzymopathy.
1.Productdeficience
Albinism
A→B→C∥D↓
PAHTyrosinaseMelaninDopaPheTyr
×2.Substrateaccumulation
Glycogenstoragedisease
A↑BC
∥D↓
3.Middleproductaccumulation
Galactosemia
AB↑C↑∥D↓4.Sideproductaccumulation
Phenylketonuria(PKU)
A→B→C∥DE↑→F↑5.Productincrease
GoutA→B→C→D↑6.Lossofnormalfeedbackinhibition
Lesch-nyhansyndrome
ABCD↓E∥㈠
Phenylketonuria(PKU)
PKU(OMIM#261600)
Animportantcauseofmentalretardation,PKUiscausedbydefectivefunctionofthe
phenylalaninehydroxylase(PAH)gene.Clinicalfeatures
1.
Mentalretardation2.“Mousy”odorinurine3.Seizuredisorder4.Hypopigmentationofskinandhair
PKUIncidence
1in16000inpopulationGenetics
Autosomalrecessive(AR),genelocation12q24,13exons,12introns,90kb,mRNA2.4kbAllelicHeterogeneity>400LocusHeterogeneitycofactBH4Basicdefect
Mutationinthegene,phenylalaninehydroxylase,whichconvertsphenylalaninetotyrosine
Phenylketonuria(PKU)
HypopigmentationofskinandhairPAHPhenyllacticacidBenzophenoneTyrosinaseMelaninDopaPheProteinTyr
ProteinPhenylpyruvicacidPhenylaceticacidMentalretardation“Mousy”odorinurine(-)(-)(-)∥↑↑↑BH4Autosomalrecessive(AR)PathologyThederivativesof
Phenylalaninedamagethedevelopingbrain,tocausethe“Mousy”odorinurineandHypopigmentationofskinandhairPrenataldiagnosis
PossiblewithDNAtechniquesTreatment
Dietaryreductionofphenylalanine
Pharmacogenetics
Thespecialareaofbiochemicalgenetics
thatdealswiththevariabilityinresponsetodrugsthatisduetogeneticvariation.Drugresponse:
absorb,transport,metabolize,reaction,excretedrugs.
Re
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