Genetic diseases

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mfawcett
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157333
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Genetic diseases
Updated:
2012-06-05 05:34:54
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genetic diseases
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genetic diseases
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  1. Familial Alzheimers
    disease
  2. 5% show autosomal
    • dominant inheritance
    • Happens when a
    • protease (γ-secretase)
    • cleaves APP (amyloid precursor protein) abnormally
    • Generation of
    • AB42 not AB40 → aggregation causes plaques
  3. 3 genes increase
    AB42:AB40
  4. APP,
    • PS1, PS2
    • Mutations/duplications
  5. Down's
    Syndrome
    Trisomy 21
  6. Turner's
    Syndrome
    XO female (no Barr bodies)

    Webbed neck, short stature, infertile
  7. Klinefelter's
    disease
    XXY males (every cell has a Barr body)

    • Tall and thin, breast development, infertile, mild
    • learning impairment
  8. Huntington's
    disease
    Autosomal dominant triplet repeat

    Prevalence 5-10/100,000

    • Neurodegenerative, chorea, diffuculties
    • swallowing/walking/eating/speaking

    Mutation in first exon of Huntingtin (chr. 4)

    polyQ expansion (CAG repeat)

    29-34: no Huntington's, next generation is at risk

    35-39: some will develop Huntington's

    >40: all will develop Huntington's


    • Mitochondria release ROSs and undergo apoptotic
    • neuronal death

    Increased [Ca]


    Normal Huntingtin

    Interacts with axonal transport machinery

    • Regulation of transcription (eg BDNF1 brain-derived
    • neurotrophic factor) and proteosome function



    Toxic gain of function


    CAG repeats unstable in DNA replication and repair

    CAG hairpin can be cleaved (good)

    • Proper strand can be cleaved and hairpin used as a
    • template (bad)


    • Length of polyQ accounts for 70% of the variance in
    • age of onset


    • Duration 10-30 years, some pharmacological intervention
    • to control movement and emotional problems
  9. Myotonic
    dystophy
    Autosomal dominant triplet repeat, shows anticipation

    Population frequency 1/8000

    • CTG expansion in 3'UTR of DMPK (dystophia
    • myotinica-protein kinase), chr 19

    Changes chromatin structure? Represses gene ecpression

    • Associated with lamin A/C at nuclear membrane (also
    • indicated in neuromuscular diseases)


    • Progressive muscle weakness esp in hands, face;
    • difficulty with relaxing grip; cataracts in mildly affected
    • individuals
  10. Fragile
    X syndrome
    X linked triplet repeat

    • Inheritance not clear: dominant in males, partially
    • dominant in females

    • 30-50% heterozygous females show the condition
    • compared to 80% males


    • Intellectual impairment, long face, large ears,
    • macro-orchidism

    CGG expansion in 5'UTR of gene coding for FMR1

    Normal: 6-52 triplets

    Affected:250-1300 triplets


    • Increased methylation in a CpG island inactivates
    • transcription of FMR1

    Shows anticipation
  11. Li-Fraumeni
    Syndrome
    • Autosomal dominant negative
    • Diagnosis:
    • sarcoma <45/ 1st
    • degree relative with cancer <45, 1st/2nd
    • degree relative with sarcoma at any age (??)

    Variable penetrance

    100% lifetime risk in women, 75% in men


    • DNA binding domain mutations prevent p53 from binding
    • to its target DNA

    • Normally one mutation is not oncogenic, but one more
    • mutation you develop (likely) will cause cancer → hence dominant
    • inheritance
  12. Marfan's
    syndrome
    Autosomal dominant negative

    Mutation in fibrillin

    • Lack of elasticity in extracellular matrix (even with
    • only one mutation)

    Aortic dissection


    Long fingers
  13. Sickle
    cell anaemia
    • Autosomal recessive
    • Mutation
    • in β-globin
    • gene at position 6

    Glu → Val (GAG → GUG)

    • Val is hydrophobic and buries itself in a pocket
    • between HbS molecules: polymers

    • Especially in deoxygenated conditions: positive
    • feedback
  14. Cystic
    fibrosis
    Autosomal recessive


    • But mutations don't have to be the same (>1400
    • found)

    1/25 Europeans are carriers


    Loss of function of CFTR channel

    Thick mucus, bacteria overgrow

    • 70-80%
    • of cases: deletion of Phe at position 506 on Chr 7 (ΔF508)

    Delays correct folding

    Degradation by quality control mechanisms


    Treatment

    Chaperones: facilitate correct folding

    • Correctors: allow partly folded CFTR to avoid quality
    • control mechanisms

    Potentiators: enhance CFTR channels already present
  15. Haemophilia
    A
  16. X linked recessive
    • 1/5000-10000 male
    • births
    • Haemorrhage may
    • occur in joints and deep muscles
    • Factor VIII to
    • treat (recombinant)
  17. Duchenne and Becker
    Muscular Dystrophy
  18. X-linked recessive
    • (but 1/3 of cases are new)
    • Mutations in
    • dystrophin
    • Usually connects
    • cytoskeleton to external basal lamina
    • 60% of mutations
    • are deletions
    • Becker:
    • maintenance of correct reading frame
    • Duchenne:
    • frameshift eg premature stop codons
  19. First disease gene
    • confirmed based on genomic position: absence of Xp21 transcript in
    • 65% of cases (cDNA probe from DMD mRNA)
  20. Leber's Hereditary
    Optic Neuropathy
  21. Deletions/point
    • mutations in NADH dehydrogenase (complex 1)
    • Blindness
  22. Kearns-Sayre
    Syndrome
  23. Range of mutations
    • to multiple ETC components
    • Problems with
    • muscles/GI/growth/cardiac/licer/respiratory/seizures/vision/hearing/
    • development/immunity
  24. Y-LINKED DISEASE
    • Deletions in AZF
    • (azoospermia) gene
    • Infertitility
    • – 5-10% of infertile men have Y linked diseases


    • Increased risk of
    • CVD
    • Only 13 common
    • Y-chrs in Western countries
    • Very little
    • recombination
    • Type 1 Y-chr
    • confers 50% higher risk of CVD by raising blood pressure and
    • cholesterol
  25. X LINKED DOMINANT
  26. Very rare
    • Hypophosphataemic
    • rickets only characterised example
    • 2x PHEX protease →
    • inactivates FGF-23 → no phosphate excretion
    • 1 mutated PHEX
    • means FGF-23 remains active and phosphate is excreted
  27. MICRODELETION
    SYNDROMES
    • Prader-Willi
    • Syndrome


    • Charcot-Marie-Tooth
    • CMT1A most common
    • form: mutation in PMP22 (major component of myelin)
    • Progressive
    • demyelination → weakness of extremities. Abnormal gait.
  28. Type 1 diabetes
  29. 2 genes with major
    • genetic contributions
    • DQB1 in MHC region
    • of chr 6 → 40% of genetic contribution
  30. asp57 allele is
    protective
  31. Locus on 11p has
    insulin gene, with a 14bp VNTR in 5' region
  32. 10% of genetic
    contribution
  33. SUMO4 associated
    with diabetic retinopathy?
  34. Wilm's tumour
    suppressor gene WT1
  35. WT1: TF,
    • recognises GC or TC rich sites
    • N terminal
    • activation domain: Pro and Glu
    • C terminal DNA
    • binding domain: 4 Zn fingers
    • Normal cells have
    • 4 alternatively spliced variants
    • Wilm's tumour:
    • childhood kidney cancer
    • Most common solid
    • tumour of childhood
  36. Frasier's
    • syndrome: gonadal dysgenesis
    • alternative
    • splice site: +KTS:-KTS is 1:2 instead of 2:1 (normal)
    • -KTS is a TF;
    • +KTS does not bind DNA, and instead processes RNA

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