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7/30/2019 Genetic basis of disease (2)
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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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MONOGENICDISORDERS
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Monogenicorsinglegenedisorders
Arecausedbyindividualmutantgenes.
Showcharacteristicpatternsofinheritance.
GenerallyfollowMendelian patternsofinheritance,
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Thereareapproximately6000singlegenedisorders.
Individuallytheyarerare,usuallyaffectingfrom1in
10 000 to 1 in 100 000.
a ena oge er ese sor ersarecommon,
affecting1%ofthepopulation.
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Apedigreeisarecordofonesancestors,offspring,
siblingsandtheiroffspringthatcanbeusedto
determinethepatternofcertaingenesordiseaseinheritancewithinafamily
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Anintroductiontopedigrees
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Anintroductiontopedigrees
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Mendelian inheritanceofsinglegene
disorders
TherearefivepatternsofMendelian singlegene
inheritance:1.Autosomal dominant
.
3.Xlinkeddominant
4.X in e recessive
5.Ylinked/holandric.
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Autosomal DominantDisorders
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AUTOSOMALDOMINANTDISORDERS
Huntin tonsdisease Chorea
Neurofibromatosistype1(NF1)
ac yonyc a congen a
Marfan syndrome
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ADDITIONALEXAMPLESOFAUTOSOMAL DOMINANTDISORDERS
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Segregationofautosomaldominantalleles
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Characteristicsofautosomaldominant
inheritance
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, , ,
neurodegenerativedisorder
, ,
dysfunction.
huntingtin geneonchromosome4.
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NEUROFIBROMATOSIS1
Neurofibromatosis1isatumordisorder.
Causedbythemalfunctionofthegeneofneurofibromin on
Neurofibromin is playingaroleincellsignalingandcontrol
ofcelldivision.
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NEUROFIBROMATOSIS1
NF1causesnoncancerouslumps.
NF1oftencomeswithscoliosis(curvatureofthespine),earn ng cu es,eyepro ems,an ep epsy.
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Is a rare enetic disorder that inherited as an autosomal
dominantmutationsingenesencodingkeratins.
MutationsinKRT6AorKRT16genesresultinPC1,whilein
.
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MARFANSYNDROME
tissue.
Resultsfrommutatedfibrillin1 (FBN1)geneon
.
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Probablesequenceofeventsinthecausationofthemajorsigns
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MARFANSYNDROME
Patientstendtobetall,withlong
limbsandlong,thinfingers.
Themostseriouscomplicationsare
defectsoftheheartvalvesandaorta.
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MARFANSYNDROME
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Autosomal RecessiveDisorders
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SINGLEGENEDISORDERS
AUTOSOMAL RECESSIVEDISORDERS
Galactosemia
Ma les ru urinedisease MSUD Phenylketonuria
Cysticfibrosis
1antitrypsindeficiency
Adenosinedeaminase deficienc
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Characteristicsofautosomalrecessive
inheritance
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Galactosemia is an autosomal recessive disorder that
affectsgalactose metabolism.
TherearetwotypesofGalactosemia
galactose1posphateuridyl transferase (fatal)
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GALACTOSEMIA Missingenzymes
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Alsocalledbranchedchainketoaciduria,isanautosomal
recessive disease.
Causedbyadeficiencyofthebranchedchain keto
aciddehydrogenase.
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PHENYLKETONURIA(PKU)(typeI).
Anautosomalrecessivedisorderthataffectsphenylalanine
me a o sm.
chromosome12.
II= Tetrahydrobiopterinreductase
I =Phenylalaninehydroxylase
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PHENYLKETONURIA
Characterizedby:
AccumulationofPhe andits
metabolites in bod fluids.
Causesseverementalretardation
ifuntreatedininfancy.
.
transportofotheraminoacids
re uiredfor roteinorneurotransmittersynthesis.
Reducessynthesisandincreases
degradationofmyelin
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SICKLECELLANEMIA
Redbloodcellsgetstuckinvesselsduetoabnormal
s ape
Codominantinheritance,disorder.
Symptomsinclude:Painepisodes,fever
Severechestpain
ChronicanemiaFatigue,Weakness
Tissuedama e braindama e
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SICKLECELLANEMIA
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SICKLECELLANEMIA
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SICKLECELLANEMIA
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CYSTICFIBROSIS CF
Alsocalledmucoviscidosis,isanautosomal
recessivedisorder.
Causedb amutationinthe eneforthec stic
fibrosistransmembraneconductance
regulator(CFTR)protein.
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CYSTICFIBROSIS CF
TheCFTRproteinisrequiredtoregulatethe
componentsofsweat,digestivejuices,andmucus.
Morethan1,000differentmutationsintheCFTR
genehavebeenidentified.
Themostcommonislossoftheentirecodon forphenylalanineatposition508(F508).
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cassette,orATPbindingcassette)superfamily oftransport
proteins.
CFTRfunctionsasachloridechannelinapicalmembranes.
thelungs,pancreas,liver,intestineandreproductivetract.
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CysticFibrosis(CF)
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Transmembraneconductanceregulator(CFTR)
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CYSTICFIBROSIS CF
CFsymptomsinclude:
Breathingproblems
Problemswithdigestion
MalnutritionSalt tastin skin
Summary of possible mechanisms involved in cells in
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Summaryofpossiblemechanismsinvolvedincellsin
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THALASSAEMIA
Agroupofinheritedautosomalrecessive diseasesthat
arecommon n e e erraneanreg on.
Causedbyeithermutationordeletionleadingto
absenceorreducedsynthesisofoneoftheglobin chains
o emog o in.
Thetwomajorformsofthedisease,alpha andbeta
thalassemias .
SS
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THALASSAEMIA
THALASSAEMIA
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THALASSAEMIA
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Thethalassaemias resultfromover150different
mutationsoftheglobin genesthatresulteitherinthe
absenceofthe lobin chains thalassaemia ora
reductionintheiroutput(+ thalassaemia).
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The thalassemias involvethegenesHBA1andHBA2.
Thalassemias resultindecreased globin production,
resultinginanexcessof chainsinadultsandexcess
chainsinnewborns.
Theexcess chainsformunstabletetramers(called
HemoglobinHorHbH of4 chains),whichhave
abnormaloxygendissociationcurves.
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Simplifiedschemeofcausationofamucopolysaccharidosis,
suchasHurlersyndrome