Genetic diseases

• dominant inheritance
• Happens when a
• protease (γ-secretase)
• cleaves APP (amyloid precursor protein) abnormally
• Generation of
• AB42 not AB40 → aggregation causes plaques

• 3 genes increase
• AB42:AB40

• APP,
• PS1, PS2
• Mutations/duplications

Trisomy 21

XO female (no Barr bodies)

Webbed neck, short stature, infertile

XXY males (every cell has a Barr body)

• Tall and thin, breast development, infertile, mild
• learning impairment

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

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

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

• 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

Autosomal dominant negative

Mutation in fibrillin

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

Aortic dissection


Long fingers

• 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

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

• 1/5000-10000 male
• births
• Haemorrhage may
• occur in joints and deep muscles
• Factor VIII to
• treat (recombinant)

• (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

• First disease gene
• confirmed based on genomic position: absence of Xp21 transcript in
• 65% of cases (cDNA probe from DMD mRNA)

• mutations in NADH dehydrogenase (complex 1)
• Blindness

• to multiple ETC components
• Problems with
• muscles/GI/growth/cardiac/licer/respiratory/seizures/vision/hearing/
• development/immunity

• 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

• 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

• Prader-Willi
• Syndrome

• Charcot-Marie-Tooth
• CMT1A most common
• form: mutation in PMP22 (major component of myelin)
• Progressive
• demyelination → weakness of extremities. Abnormal gait.

• genetic contributions
• DQB1 in MHC region
• of chr 6 → 40% of genetic contribution

• asp57 allele is
• protective

• Locus on 11p has
• insulin gene, with a 14bp VNTR in 5' region

• 10% of genetic
• contribution

• SUMO4 associated
• with diabetic retinopathy?

• 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

• 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