Week 6 - Huntington’s Disease Flashcards
1
Q
How is Huntington’s Disease diagnosed?
A
- medical history
- family history
- neurological examination
- brain imaging test
- labaratory tests
- genetic test (to confirm)
2
Q
What is the structure of the Huntington disease gene?
A
- trinucleotide repeats
- size of repeats varies
- when number exceeds threshold
- neurological disease happens
- CAG glutamine produces polyglutamine (polyQ) tract
3
Q
What are the advantages of predictive testing?
A
- uncertainty of gene status removed
- negative result
- concerns reduced
- positive result
- make future plans
- arrange treatment if available
4
Q
What is a predicitive test?
A
genetic test for an asymptomatic individual to predict future risk
5
Q
What are the disadvantages of predictive testing?
A
- positive result
- removes hope and creates uncertainty of when and if
- impact on family and friends
- potential problems with insurance and mortgage
- negative result
- survivor guilt
6
Q
What is an exclusion test?
A
- DNA markers used to identify patterns as they pass down
- samples from at least two generations
- distinguish between results of low chance of inheritance instead of 50%
7
Q
What is PGD?
A
- Pre-implantation Genetic Diagnosis
- when one parent has inherited HD
8
Q
What is TP-PCR?
A
- Triplet Primed PCR
- indicates presence/absence of expansion
- not size
- reverse primer hybridises to sequences downstream and adjacent to end of tract
- or randomly across
- extended reverse primers generated
- serve as primers
- various product sizes are produced
- stutter pattern on electrophoresis
9
Q
How does triplet repeat tract cause HD?
A
- gene encodes huntingtin protein
- caspase 3 targets it
- for neuronal apoptosis
- molecular stutter results in polyQ stretch
- longer protein accumulation leads to cell death
- abnormal conformation/folding of protein
- mutant protein binds to transcriptional regulators
- loss of normal function
- interferes with other proteins
10
Q
How can enhanced refolding target mHTT?
A
- activate Heat Shock transcription Factor 1 (HSF1)
- upregulation of chaperones
- increases protein-folding
- inhibit HSP90
- to stop HSF1 inhibition
- suppresses mHTT formation
11
Q
How can ASOs treat HD?
A
- AntiSense Oligonucleotides
- prevent translation
- bind to HTT mRNAs
- RNase H-mediated degradation
12
Q
How can siRNAs treat HD?
A
- silence mRNAs through RNA-Induced Silencing Complex (RISC)
- creates off target effects and toxicity
- single stranded forms have lower potency
- probable reduced side effects
- can target HTT mRNA
- processed by cellular machinery leading to incorporated RISC
- promotes silencing
13
Q
Why do trinucleotide repeat disorders occur?
A
errors made during DNA replication
