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GeneticBasisofDiseases
assan re s e . .
epartmento oc em stry
FacultyofMedicine
Internationa Universityo A rica,K artoum,Su an
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Understandthecommonprocessesthatleadto
mu agenes s
Appreciatehowdifferentclassesofmutationsyield
differenteffectsonproteinstructureandfunction.
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Drawoutexamplepedigrees representing
. ,
2. autosomal recessive,
3. Xlinkeddominant,
. ,
5. andmitochondrialinheritance.
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Appreciatetheconceptofheritabilityinthecontextof
complexdiseases.
Identifythecommonchromosomaldisordersand
defineaneuploidy,triploidy,trisomy andmonosomy,withexamplesofdiseases.
describefeaturessuggestiveofinheritedcancer
susce tibilit .
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Geneticdisordersareillnessescausedby
a norma es ngene csequencesan e
chromosomestructures.
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Burden
Althougheachgeneticdisordermayberare,
.
Canaffectanybodysystemandhaveamajorimpactonbothmorbidityandmortality.
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Importanceofmedicalgenetics
Anunderstandingofgeneticsisimportant,notonly
forthediagnosis andmanagement ofsuch
disorders,butalsofortheidentificationofgenetic
.
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Mutationsarepermanent inheritablechangesinthe
amoun ors ruc ureo gene cma er a .
Theycanbeinherited oroccurspontaneously and
canbesubdividedintogermline (gametes)or
somatic mutations.
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Mutationplaysakeyroleinthepathogenesisof
gene c sor er, ya er nggenesequencesan
their rotein roducts.
Defectivegene
defectiveprotein
alteredfunction disease
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Atthesinglegenelevelmutationsmayresultfrom:
substitution(pointmutation)
inversion
tripletrepeatexpansion.
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Pointmutationsmayariseasaresultof:
1. ErrorsinDNAreplication.
. e ec verepa ro amage .
.
cytosinetothymine(mostcommon).
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Substitutionsareclassifiedas:
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Pointmutationsmaybesilent ordeleterious
epen ngupon e r ypean s e.
Rarely,amutationmaybeadvantageous andfavored
bynaturalselection.
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Mutations
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DeletionislossofDNAinvolvingfromonetomany
ousan so asepa rs.
Sequencesattheendsofdeletionsareoftensimilar,
predisposingtorecombinationerrors.
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Insertion isagainofDNA.
, ,
basesandrepeatedmotifspredisposetoduplication
byreplicationslippage
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Theeffectsontheproteinofdeletionandinsertion
dependon:
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Deletion, Alports syndrome,ahereditarydiseaseof
asemen mem ranes,c arac er ze y
sensorineural deafnessandrenalfailure.
Duplication,Duchenne musculardystrophy(DMD).
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Inversionsmayinvolveanythingfromtwotomany
thousandsofbasepairs.
The occur in areas ofse uence homolo
(sequencesateachendoftheinvertedsegmentoftenresembleeachother .
,
inversionofseveralhundredthousandbasepairs
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r p e or r nuc eo e repea expans onsare
typicallyinvolvingCGrichtrinucleotides (CGG,CCG,, .
Tripletexpansionresultsinadefectivegeneproduct,yieldingdisease.
autosomally dominant orrecessive manner,orbeX
.
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Friedreichs ataxia resultsfromanexpansionofthe
.
orma yt ereare to cop eso t str nuc eot e,
patientsmayhaveasmanyas1000.
Thisexpansionisintronic andisthoughttomaketheDNAsticky,interferingwiththeprocessof
transcription.
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Structuraleffectsofmutation
onprotein
Silentmutations
Silentmutations,pointmutations,havenoeffectontheaminoacid sequenceofaprotein.
Consideredtobeevolutionaryneutral,butrecently
differentialsplicing.
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Structuraleffectsofmutation
onprotein
Abasechangealtersacodon,incorporationofadifferent
.
u u
uponitslocationrelevanttothetertiaryorquaternary
a so epen onw e er e woam noac s nvo ve
arefromthesameordifferentgroups(i.e.hydrophobicor
.
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Structuraleffectsofmutation
onproteinxammp e
Insic ece isease,t esu stitutiono A yTatt e17thnucleotideofthe globin genechangesthecodon
.
stabilityoftheprotein.
Haemoglobin formspolymersunderconditionsoflowox entension,leadin tosicklin ofredbloodcells.
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Structuraleffectsofmutation
onprotein
Nonsensemutations
Nonsensemutationsarepointmutationsthatleadto
the conversion of a codon to a sto codon UAG
UAA,UGA).
Theyleadtoatruncated protein,withthosethat
occurearlyinagenesequencehavingahigher
probabilityofcompletelyinactivatingagene.
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Structuraleffectsofmutation
onprotein
Insertionsan e etionso nuc eoti es,i notamultipleofthree,leadtoframeshiftmutations,
Theopenreadingframeofthegeneandthecorrespon ngam noac sequence sa tere ,
Leadingtocompleteinactivationofthegene.
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Functionaleffectsofmutation
onprotein
Withtheexceptionofimprintedgenes,genesonboth
thematernalandpaternalchromosomesareexpresse .
Ifeitherthematernalorthepaternalgenecontainsamutation,thecellwillexpresstwodifferentprotein
products.
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Functionaleffectsofmutation
onprotein
Mutationsexerttheirphenotypiceffectsbyoneoftwomechanisms:
1. lossoffunction
2. orgainoffunction.
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Functionaleffectsofmutation
onprotein
Lossoffunctionmutations
Amorphic mutationalsoknownasnull
mutations are associated with a com lete
absenceofgeneproductfunction.
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Functionaleffectsofmutation
onprotein osso unct onmutat ons
Hypomorphic mutation,alsoknownasleakymutations,leadtoapartiallossoffunction.
Theyusuallyresultfrom:
1. analteredaminoacidthatmakesthepolypeptidelessactive.
2. areductionintranscriptionthatresultsinlessnormaltranscript.
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Functionaleffectsofmutation
onprotein
T emajorityo eterozygousstatesare ap osu c ent;
thatisonefunctionalcopyofageneisadequateforthe
w y y .
Theterm haploinsufficiency is asituationwherebya
reductionof50%ofgenefunctionresultsinanabnormal
p eno ype.
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Functionaleffectsofmutation
onprotein
T esemutationsresu tineit er:
increasedactivityofthegeneproduct(hypermorphic)
Orthe ainofanovelfunctionoranovel atternof
geneexpressionofthegeneproduct(neomorphic).
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Functionaleffectsofmutation
onprotein
Trinuc eoti e repeatexpansionsrepresentgaino
functionmutations.
Usuallyatoxicgainofproteinfunction,which
predisposestoproteinmisfolding andprotein
aggregationandleadstoneurodegeneration.
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Functionaleffectsofmutation
onprotein Dominantnegativemutations
Dominantnegativemutationsarealsoknownas
antimorphic mutations.
heterozygoteadverselyaffectsthenormalgene
,inactivatingit.
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Functionaleffectsofmutation
onprotein Dominantnegativemutations
Theclassicalexampleisthatofanaminoacidchange
thatpreventsapolypeptidefromfunctioningina,
Marfansyndrome.