genetic basis of diseases, chromosomal aberrations

7/31/2019 Genetic Basis of Diseases, Chromosomal Aberrations

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GeneticBasisofDiseases

assan re s e . .

epartmento oc em stry

FacultyofMedicine

InternationalUniversityofAfrica,Khartoum,Sudan


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Ageneticdiseasesresultsfromabnormalitiesinan

' .

Abnormalitiescan

range

from

asingle

base

mutation

in

a

gene o ea onor e e ono anen re

chromosomeor

set

of

chromosomes.


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Typesofgeneticdiseases


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MolecularBasis

OfDiseases

Changesanenzyme

Phenylalaninehydroxylase (PKU)

Environment

Andgenes Changesanenzymeinhibitor

1Antitr sin. Im aired secretion from liver

toserum(Emphysemaand Liverdisease)Growthregulation

Rb causing

DefectedLDLreceptor

(Familialhypercholesterolemia)Changesinstructural

Changeatransportorcarrierprotein

1.Haemoglobin,mutationsinsplicesitesleadsto

, . .

1.Collagen,

disorders

that

produceabnormalorreduced

amount of colla enreducedglobin chain(Thalassemia) ,or

deletionoftheglobin gene(Thalassemia) .

2.Defected

cystic

fibrosis

transmembrane

(Osteogenesis imperfecta)

2.Defectedfibrillin ene

Con uctanceRegu ator Cystic i rosis .

ChangesinHaemostasis

(Marfansyndrome)

3.DeletionofdystrophingeneFactorVIII e etions,insertions,nonsense

mutationreduce

synthesis

or

abnormal

factor

VIIICausingHemophiliaA.

(DuchenemuscularDystrophy)


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Chromosomaldisorders


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Whenanindividualismissingeitherachromosome

fromapair

(monosomy)

or

has

more

than

two

chromosomesofapair(trisomy).

Examples

. , .

2. TurnerSyndromeisanexampleofmonosomy,afemale

.


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Thiscantakeseveralforms:

1. Deletions.

2. Duplications.3. Translocations.

4. Inversions.

5. Rings.


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Deletions: Aportionofthechromosomeismissing

ordeleted.

Duplications: Aportion

of

the

chromosome

is


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StructuralAbnormalities:

Translocations: Whena ortionofonechromosomeis

transferredtoanotherchromosome.

Therearetwomaintypesoftranslocations.

1. Inareciprocaltranslocation,segmentsfromtwo

.

2. InaRo ertsonian trans ocation,anentire

chromosomehasattachedtoanotheratthe

cen romere.


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Inversions: Aportionofthechromosomehasbrokenoff,

turnedupside

down

and

reattached,

therefore

the

gene cma er a s nver e .

Rings: A

portion

of

achromosome

has

broken

off

and

formedacircleorring.Thiscanhappenwithorwithout

osso geneticmateria .


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Chromosomeabnormalitiesusuallyoccurwhenthereis

anerror

in

cell

division.

Therearetwokindsofcelldivision.

Mitosis

Meiosis


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Errorsincelldivisioncanresultincellswithtoofewor

.

Errors

can

a so

occur

w en

t e

c romosomes

are

eing

duplicated.


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Factorsthatcanincreasetheriskofchromosome

abnormalitiesare:

birthto

babies

with

chromosome

abnormalities

than

oun erwomen.

Environment: mayplayaroleintheoccurance ofgenetic

errors.


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Nondisjunction

Nondisjunction isthefailureofchromosomepairsto

.

toseparate

in

meiosis

I, or

the

failure

of

sister

chromatids

to

se aratedurin meiosisIIormitosis.

Theresult

of

this

error

is

acell

with

an

imbalance

of

chromosomes.


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Nondisjunction

Whenachromosomeislost(2n1),monosomy, the

daughtercell(s)willhaveonemissingchromosome.

Whenachromosomeisgained,trisomy,thedaughter

cell(s)willhaveoneadditionalchromosome.

Theriskofnondisjunctionincreaseswithmaternal

ageatpregnancy,withabout31yearsbeingthe

average.


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1. Downsyndrome,

2. TripleXsyndrome,

3. Klinefelter's Syndrome

'. .


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.

Istypicallycausedbynondisjunction duringthe

ameto enesis.

growthas

well

as

facial

appearance.

Canbeidentifiedinthe1st trimesterofpregnancy

amniocentesis .


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Nondisjunction ofchromosome21leadingto

ownsyn rome


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Akaryotype of DownsSyndrome


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, InrarecasesDownsyndromeiscausedbya

Robertsonian translocation.

The carrier of Robertsonian translocation will not have

Downsyndrome,

but

can

produce

children

with

Down

s ndrome.


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14;21Robertsonian translocationcarrier


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DOWNSYNDROME Characteristics

1. Shortstature.

2. Flatfacialprofile.

3. Hypotonia,laxjoints,transverse.

(simian)palmar crease.

4. Congenitalcardiacdefects(incomplete

septation).

5. Menta retar ation.

. .


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Klinefelter's syndrome(47,XXYorXXY)

Causedbynondisjunctionofsexchromosomes,extraX

c romosome XXY .

Itisthesecondmostcommontrisomy.

Itexists

in

roughly

1out

of

every

1000

males,

and

one

nothavethesyndrome.


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'

Affectedindividuals aretall,usuallydon'tdevelop

secondarysex

characteristics

(facial

hair

and

pubic

hair).

Primarilyaffects

the

testes,

and

the

production

of

s ermsandtestosterone.

( )


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Karyotype ofKlinefelter's syndrome(47,XXY)


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TURNERSYNDROME

ause ynon s unc ono

chromosomes(monosomy).

Theoffspringare(XO)femaleshaving

.

,

arecommonfeatures

Affectedwomenareusuallysterile.


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Turners syndrome


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Turnerssyndrome


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thepresenceofanextraXchromosome.

AlwaysproducesfemaleswithXXX.

A mosaic form also occurs where onl a ercenta e of

bodycellcontainXXXwhiletheremaindercarryXX.


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,

activeatanytime.

Thus,TripleXsyndromemostoftenhasonlymild

effects,

or

no

effects

at

all.

TripleXgirlssufferfromanxietyandbeveryshy,and

this ma affect their social and academic life.


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, , , .

Veryrarechromosomaldisorder(only60cases

worldwide)

Characterized b the resence of two additional X

chromosomes.

Causedbydefectinmeiosis.


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,

, .

Isveryrarechromosomaldisorder(only25cases

worldwide)

Characterized b the resence of three additional X

chromosomes.

Causedbydefectinmeiosis.


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,

Patau syndrome,alsoknownastrisomy 13

Causedbynondisjunctionofchromosomesduring

.

SomearecausedbyRobertsonian translocations.

Patau syndromeaffectsapproximately1in25,000

livebirths.


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Pataus Syndrome,


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EdwardsSyndrome(Trisomy 18)

Iscausedbythepresenceofallorpartofanextra18th

.

Itisthesecondmostcommonautosomaltrisomy,after

DownSyndrome,thatcarriestoterm.

Theincidenceofthesyndromeisestimatedas1/3,000

livebirths.

Likeothertrisomies,theincidenceincreaseswiththe

' .


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survival(about95%dieinutero).

Deathsresults

from

heart

and

renal

defects.

EdwardsSyndrom

Ofliveborn infants,only50%liveto2months,and

only510%willsurvivetheirfirstyearoflife.


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Diseasesresultingfromstructuralbonrmalities

nc u e:

1. CriDuChatS ndrome

2. WilliamsSyndrome

3. FragileXsyndrome

.


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CRIDUCHATSYNDROME

Iscausedbyadeletionontheshortarmofchromosome

5leadingtolossofmultiplegenes.

Affectedbabiesareusuallysmallatbirth,andhave

' ,

catlikecry.


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CRIDUCHATSYNDROME

Round face

A smallchin

Widely seteyes

Foldsofskinovertheireyes

A

small

bridge

of

the

nose.


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WILLIAMSSYNDROME

Isadisorderthatresultsfrombreakof

chromosome7,includingthegeneelastin.

Themostcommonsymptomsare:

mentalretardation

heartdefects

unusualfacialfeatures(smallupturnednose,w emou , u ps,sma c n,

widelyspacedteeth).

Fragile X syndrome (or Martin Bell syndrome)


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FragileXsyndrome(orMartinBellsyndrome)

Thesyndromeisassociatedwiththeexpansionofasingle

trinucleotide genesequence(CGG)ontheXchromosome.

ResultsinafailuretoexpresstheFMR1(fragileXmental

retardation1)protein whichisrequiredfornormalneural

development.

ereare

our

orms

o

rag e

syn rome

w c

re ate

to

thelengthoftherepeatedCGGsequence.


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Fragi eXsyn rome

F il X d


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FragileXsyndrome

Physicalcharacteristicsinclude:

Prominentears

Longface(verticalmaxillaryexcess)

Higharchedpalate

Hyperextensible fingerjoints

Doublejointedthumbs

a ee

Softskin

Lowmuscletone

genetic basis of diseases, chromosomal aberrations

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