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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.