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MED310 > Lecture 3 > Flashcards

Lecture 3 Flashcards

1
Q

Repeat expansion Disorders:

A
  • Diseases caused by expansion of repetitive DNA sequences
  • Initially triplet repeat/trinucleotide repeat expansions (FXS, SBMA, DM, HD etc.)
  • Penta- (SCA10 & SCA31), hexa- (SCA36 & ALS/FTD) & more complex (EPM1) pathological expansions exist
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2
Q

Repeat expansion disorders are…

A

Most autosomal dominant and GOF- \Look at diarma

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3
Q

What are the two main types of effect of mutations ( at what level) ?

A

Protein or RNA

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4
Q

Disease causing expansion

A

can occur throughout gene

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5
Q

Fragile X syndrome –

A

• X-linked condition
- fully penetrant males
- ~50% penetrance females
• Long face, protruding ears, low muscle tone, macroorchidism(large testicles)
• Learning disabilities – normal IQ to severe mental retardation
• Cytogenetic abnormality 1969
• FMR1 cloned 1991

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6
Q

FMRP-

A
  • FXS caused by loss of FMRP function
  • RNA-binding protein
  • Associated with polyribosomes & mRNA granules transported to synapses and translation response to neural activity
  • Functions as translational repressor, stalls protein synthesis during mRNP transport
  • Important for LTP, learning & memory
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7
Q

Long expansion in FMRP causes what ??

A

Fragile X syndrome

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8
Q

Different lengths expansions

A

Give different diseases

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9
Q

FXTAS-

A

• 55-200 CGG repeats in FMR1
• Late onset, >50
• Intention tremor & ataxia
• White matter lesions middle cerebellar peduncle
• Ubiquitinated inclusions
• Normal FMRP levels → RNA toxicity
Protein still made inspite of long repeats GOF via RNA toxicity whereas fragile X is LOF

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10
Q

What is the effect of really long repeats ?

A

Interfere with the transcription and translation

- LOF no protein e.g Fragile X syndrome

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11
Q

Polyglutamine disorders-

A
  • CAG triplet repeat expansion disorders
  • 1991 - spinobulbar muscular atrophy (SBMA) or Kennedy’s disease
  • 1993 - Huntington disease (HD) high prevalence in caucasions
  • 1994 - Dentatorubral-pallidoluysian atrophy (DRPLA) Japanese equivalent of Huntingtons – low prevalence in the uk
  • 1993-2001 - spinocerebellar ataxia (SCA) types 1,2,3,6,7 and 17 ( now over 50)
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12
Q

Common features of polyglutamine diseases-

A

• Autosomal dominant inheritance (except SBMA – X-linked recessive)
• Genetic anticipation (next slide)
• Inverse relationship between CAG repeat length and age of onset
• Toxic “gain of function” mechanism
• Protein accumulation and aggregation
Repeat gets longer age of onset gets earlier

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13
Q

Polyglutamine diseases show genetic anticipation-

A

• Age of onset becomes earlier in successive generations
• Mainly associated with paternal transmission
• Explained by inter-generational repeat expansions during spermatogenesis
As repeat get longer during generations the age of onset gets longer

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14
Q

Huntington disease (HD)-

A
  • Huntington’s chorea described in 1872 by George Huntington
  • Hereditary progressive neurodegenerative disorder
  • Fatal - death usually 15-20 y after onset
  • Frequency 4-10/100,000
  • Autosomal dominant inheritance (before mendels work)
  • Penetrance nearly 100%- very likely for disease to manifest if you have a long enough life span
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15
Q

HD Pathology-

A
  • Severe atrophy of the striatum
  • Cortical atrophy – overall reduction in brain size
  • Loss of GABAergic medium-sized spiny striatal neurones (MSN)
  • Juvenile cases more severe - widespread neuronal loss ( in cerebellar)
  • Astrogliosis and microglial activation
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16
Q

Neuronal loss in the Striatum
Caudate nucleus doesn’t bulge into internal capsule/lateral ventricle
Huge neuronal loss in the caudate
are pathological signs of what disease ??

A

Huntingtons

17
Q

HD geen and mutation

A

Tend to occur through paternal transmission

18
Q

Toxic gain of function mechanism-

A

• Htt knockout embryonic lethal E7.5
• +/- mice normal – not haploinsufficiency
• Rescue embryonic lethality by breeding +/- mice with 72Q YAC transgenics
- 72Q/- mice develop normally, show HD-like symptoms as adults

19
Q

evidence for GOF

A

Yac can rescue embryonic lethal phenotype –

20
Q

HTT aggreagation

A

Htt protein aggregation in HD cortex-
Aggregates detected with anti-huntingtin or anti-ubiquitin antibodies
Range of nuclear and cytoplasmic pathology
No direct correlation between aggregation and neuronal

21
Q

Protein sequestration-

A
  • Many proteins (especially transcription factors) have long (15-42) non-pathological polyglutamine tracts
  • Proteins with non-pathological polyglutamine tracts (e.g. TBP & CBP) can be sequestered into mutant polyglutamine aggregates
22
Q

Transcriptional dysregulation in HD-

A
  • CREB-binding protein (CBP) - transcriptional co-activator
  • Present limiting amounts in cells
  • Possesses histone acetyltransferase (HAT) activity
  • Decreased histone acetylation & global dysregulation of transcription seen in HD
23
Q

Histone deacetylase (HDAC) inhibitors as potential therapeutic agents in what disease ??

A

HD

-Silence genes using HDAC inhibitors

24
Q

SBMA-

A
  • Adult onset neuromuscular disease
  • Muscle weakness and wasting especially in the extremities, face and throat
  • Speech & swallowing difficulties, muscle cramps
  • Degeneration of spinal and bulbar motor neurones
  • Normal lifespan unlike ALS
  • CAG repeat expansion in androgen receptor
  • X-linked recessive – why? Whereas all others autosomal dominant ?!
25
Q

Examples of neurodegenerative & neuromuscular disorders caused by non-coding repeat expansions

A

• Myotonic dystrophy
• Fragile X-associated tremor/ataxia syndrome – 60-200 CGG in 5’-UTR of FMR1
• Spinocerebellar ataxia 8, 10, 12, 31 & 36
• ALS/FTD – intronic GGGGCC in C9ORF72
Pathological non-coding repeat expansions tend to be longer than disease-causing coding repeat expansions

26
Q

Myotonic dystrophy-

A

• Autosomal dominant neuromuscular disease
• Multisystemic – muscle, cardiac, cognitive, behavioural, eye, endocrine symptoms
• 1:20,000 births
• Congenital, childhood & adult forms – dependent on repeat length
Longer repeat length earlier onset

27
Q

Myotonic dystrophy genetics-

A
  • DM1 CTG expansion in 3’-UTR of DMPK
  • DM2 CCTG expansion in 1st intron of CNBP/ZNF9
  • DM1 more common
  • Genetic anticipation seen in DM1, mainly maternal transmission
28
Q

Mechanisms of non-coding repeat toxicity-

A 
•	RNA foci/protein sequestration
- splicing (DM)
- nucleocytoplasmic transport (ALS/FTD)
•	Repeat-associated non-AUG translation (RANT)
•	Haploinsufficiency
29
Q

Myotonic dystrophy is an example of what opathy ?

A

Spliceopathy

30
Q

Experiment to show why SBMA is X linked ?

A

Overexp 97 glutamine expressed phenotypes
Early on off spring maintained weight other did not
Severely affected males

Aggregated proteins – stuck in the well
Aggregated in nucleus- pathologically different in males then females
Castration – removal of testosterone phenotype is rescued
Dragging feet but better after castration
Sham operated protein accumulation
Castration – ameliorate phenotype
Testosterone induces symptoms and pathology in 97Q females
All phenotypes shown in males induced in females

31
Q

SBMA

A

Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy

MED310 (18 decks)

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