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