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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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DISORDERS

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SINGLEGENEDISORDERS

AUTOSOMAL CODOMINANAT DISORDERS

Familialhypercholesterolemia.

.

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FHisanautosomalcodominant disorder

Causedbyalargenumber(>900)ofmutationsinthe

LDL rece tor ene on chromosome 19.

arac er ze ye eva e p asma eve so

withnormaltriglycerides,tendonxanthomas,and

.

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Isaveryrareautosomalcodominant disorder

CausedbymutationsinthegeneencodingABCA1.

ABCA1isacellulartransporterthatfacilitateseffluxof

unes er e c o es ero an p osp o p s romce s

toapoAI

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.

Thediseaseischaracterizedby:

1. Cholesterolaccumulationinthe

reticuloendothelial system2. He atos lenome al

3. Enlarged,yellowororangetonsils.

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TANGIERDISEASE

Thecholesterolefflux

necessaryforthetransferof

freecholesterol(FC)and

phospholipid (PL)outofcells.

Itbelongstothefamilyof

ATPbindingcassettetransporter

Source:James

Scott

Nature

400,

816

819(26

August

1999)

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CODOMINANCE

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XlinkedDisorders

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SINGLEGENEDISORDERS

SEXLINKED

XLINKEDDISORDERS

Severecombinedimmunodeficienc .

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SegregationofanXlinkedrecessiveallelewhen

themother

is

acarrier

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SegregationofanXlinkedrecessiveallelewhen

thefather

is

affected

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traitcharacterizedbydecreasedabilitytoperceivecolor

differences.

deficiencies:monochromacy,dichromacy, andanomalous

trichromacy.

Man ofthe enesinvolvedincolorvisionareontheX

chromosome,makingcolorblindnessmorecommonin

malesthaninfemales.

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DMD anX n e recess vemuscu ar ystrop y

associatedwithmutationsinthedystrophin geneinthe.

Dystrophin isanimportantstructuralproteinwithinmuscletissue.

DMDischaracterizedbyrapidmuscledegenerationleadingtolossinambulation,respiratoryfailureand

death.

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Summaryofmechanismsinvolvedinthecausation

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DUCHENNE MUSCULARDYSTROPHY(DMD)

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haemophilia A,haemophilia BandvonWillebrand disease.

Symptoms

Thesymptomsofhaemophilia aremainly:1. Prolon edbleedin fromin uries.

2. Frequentorheavynosebleeds.

3. Tracesofbloodintheurine.4. Heavymenstrualbleedinginfemales.

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Haemophilia A isthemostcommon(80%ofcases)

bleedingdisorderaffecting 1in5000males.ItisanX

linkedrecessive disorderduetodeficiencyof

coagulationfactorVIII.

locatedontheXchromosomeatXq28withpoint

.

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Haemophilia B islesscommon(20%ofcases)than

inheritance,andisduetomutationsinthefactorIX

.

u a ons n sgeneareusua ypo n mu a onsor

smalldeletionsorduplications.

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Haemophilia Cisanautosomaldisorder(notXlinked)due

tolackoffunctionalclottingFactorXI.

ThegeneforfactorXIislocatedonchromosome4anditis

notcompletelyrecessive,i.e.individualswhoare

heterozygousalsoshowincreasedbleeding(doeseffect)

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.

Itiscause y e iciencyo vonWi e ran actor

requiredforplateletadhesion

TherearethreetypesofhereditaryvWD,TypeI,IIand

III.

WithinthethreeinheritedtypesofvWD thereare

various subt es.

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vonWillebrand

inheritedinanautosomal

dominant pattern.

TypeIIIisinheritedas

autosoma recess ve.

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Xlinkeddominantdisorders

disorderthataffectsbothhemizygous malesand

heterozygousfemales.

(vitaminDresistantrickets)andoculomotor

nystagmus.

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Xlinkeddominantdisorders

Thegeneistransmittedthroughfamiliesinthe

samewayasXlinkedrecessivegenes:females

theirdaughters;malestransmitthemutationtoall

theirdaughtersandnoneoftheirsons.

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ArecausedbymutationsingenesontheXchromosome.

OnlyafewXlinkeddominantdisordershavebeen

recognized.

Malesaremorefre uentl affectedthanfemales

menandwomen.

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notbeaffected,andhisdaughterswillallinheritthe

condition.

chanceofhavinganaffecteddaughterorsonwitheachpregnancy.

SomeXlinkeddominantconditions suchasAicardisyndrome,arefataltoboys,andonlyseeningirlsandboys

withKlinefelter syndrome.

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XSCID alsocalledAlymphocytosis,orGlanzmannRiniker

syndrome.

Itisasevereheritableimmunodeficiencyduetoadefectin

oneofseveralpossiblegenes.

MostcasesofXSCID areduetomutationsinthegene

encodingthecommongammachain(c),aproteinthatissharedbythereceptorsforseveralinterleukinsleadingto

completefailureoftheimmunesystem.

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ThesecondmostcommonformofSCIDafterXSCIDis

causedbythedeficiencyofadenosinedeaminase (ADA),w c ca a o ze pur nes.

SCIDisanautosomal

recessive

metabolicdisorder.

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SummaryofprobableeventsinthecausationofSCIDdueto

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LackofADAcausesaccumulationofdATP whichinhibits

theactivityofribonucleotide reductase.

Ribonucleotide reductasegeneratesdRNT requiredfor

lymphocyteproliferation.

LackofdRNT inhibitslymphocyteproliferationand

compromisetheimmunesystem.

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Aicardi Syndromeisararegeneticmalformation

syndromecausedbyadefectontheXchromosome.

Characterizedbythepartialorcompleteabsenceof

thecorpuscallosum.

Aicardi syndromehasonlybeenobservedingirlsorin

' .

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YlinkedDisorders

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SINGLEGENEDISORDERS

SEXLINKED

YLIKEDDISORDERS

MaleInfertilit .

Hypertrichosis pinnae (Excesshairontheear).

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n e sor ersarecause ymu a onson e

chromosome.

InYlinkedinheritance,onlymaleswouldbeaffected.

TransmissionisfromafathertoallsonsviatheY

chromosome

ThemaingeneinYchromosomeistheSRYgene,which

.

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Hypertrichosis pinnae

Excessivehairontheearpinna

Ylinkedgeneticdisorder

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disorders

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Genetic isor ersmaya so ecomp ex,mu ti actoria or

polygenic,thismeansthattheyarelikelyassociatedwiththe

effectsofmultiplegenesincombinationwithlifestyleand

environmenta actors.

Multifactoral disordersincludeheartdiseaseanddiabetes,

goutandtheyoftenclusterinfamilies.

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multiplegenes,oftencoupledwithenvironmental

.

2. HYPOTHYROIDISM

3. COLONCANCER

4. BREASTCANCERANDOVARIANCANCER5. ALZHEIMER'SDISEASE

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GOUT HYPERURICEMIA

Goutisagenetic/acquireddisorderofuricacidmetabolism

thatleadstohyperuricemia.

arthritis.

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GOUT HYPERURICEMIA

Theoccurrenceof outis artl enetic contributin to

about60%ofvariabilityinuricacidlevel.

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Themostcommoninheritedformofhypothyroidismis

adefectoftheTPO(thyroidperoxidase)geneon

c romosome .

Thisgeneplaysanimportantroleinthyroidhormone

production.

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TheBRCA1andBRCA2genesarecalledtumor

suppressorgenesbecausetheyprevent

uncon ro e ce grow .

BRCA1islocatedonchromosome17,andBRCA2

islocatedonchromosome13.

ScientistsbelieveBRCA1andBRCA2workby

fixingdamagedorbrokenDNA.

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WomenwhoinheritamutatedcopyoftheBRCA1or

chromosomes,andthereforehaveagreaterchanceof

accumulatingmutationsthatwillleadtouncontrolled

ce grow an cancer.

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'

Alzheimer'sisadiseasethatcausesdementia,orlossof

brainfunction.

Itaffectsthepartsofthebrainthatdealwithmemory,

thought,andlanguage.

Mutationsingenesfoundonchromosomes1,14,and21

arelinkedtorarerformsofthedisease,whichstrike

earlierinlife.

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MitochondrialInheritance

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. .

2. Has37genescodefor13proteins,ribosomalRNAand

transferRNA.

3. Thegeneticcodeisdifferentfromtheuniversalcode.

.

mutantmitochondrialgenes.

MITOCHONDRIALDNA:

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Thistypeofinheritance,alsoknownasmaternal

inheritance,appliestogenesinmitochondrialDNA.

Becauseonlyeggcellscontributemitochondriatothe

developingembryo,onlyfemalescanpasson

mitochondrialconditionstotheirchildren.

AnexampleofmitochondrialdisorderistheLeber's

HereditaryOpticNeuropathy(LHON)

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'

LHONisusuallyduetooneofthreepathogenic

mitochondrialDNA(mtDNA)pointmutations.

Thesemutationsaffectnucleotidepositions11778,3460

and14484,respectivelyintheND4,ND1andND6

subunitgenesofcomplexIoftheoxidative

p osp ory at on c a n nm toc on r a.

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'

LHONischaracterizedbydegenerationofretinalganglion

cells and their axons which leads to an acute or subacutelossofcentralvision

Itaffectspredominantlyyoungadultmales.

Leber'sHereditaryOptic

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y p

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Reference

1. Helen

M

Kingston,

ABC

OF

CLINICAL

GENETICS,

Thirdedition2002,London