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Lecture 17 Flashcards

1
Q

What are some diseases of under expression or impaired function of RNA/protein?

A
  • Cystic fibrosis
  • Becker muscular dystrophy
  • Spinal Muscular Atrophy
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2
Q

What are some diseases of over expression/gain of function of RNA/protein?

A
  • Motor neuron diseases

- Huntington’s

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3
Q

What are some diseases due to loss of function of RNA/protein?

A
  • SCID-X1
  • Duchenne Muscular Dystrophy
  • Cystic Fibrosis
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4
Q

Define direct treatments

A

(molecular) treatments to address underlying cause

- -> mutation dependent

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5
Q

Define indirect treatments

A

Doesn’t treat underling cause, instead aims to improve quality of life/comfort/function

e. g.
- conventional trials (clinical)
- reduce inflammation/fibrosis
- Improve muscle repair/incr. protein synth.
- normalise calcium metabolism

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6
Q

What are the 5 types of genetic diseases?

A
  1. Monogenic (CF)
  2. Complex (Asthma, Alzheimer’s, Heart Disease)
  3. Cancer (p53, BRCA mutations)
  4. Autoimmune Diseases
  5. Viral Infection
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7
Q

What is the level of interplay between genotype and environment in Monogenic diseases?

A

90% genetic

10% environment

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8
Q

What is the level of interplay between genotype and environment in Complex diseases?

A

75% genetic

25% environment

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9
Q

What is the level of interplay between genotype and environment in Cancer?

A

50% genetic

50% environment

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10
Q

What defines a rare disease?

+ characteristics

A

Affects <1/2000 people

  • candidates for genetic therapies
  • 8000 rare diseases
  • affect 8% population
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11
Q

What are the 2 prospects for therapy?

A

1) Pathogenesis
o Which cells/tissues are affected

2) Diagnosis
o Can the disease be accurately diagnosed?
o Time of diagnosis?
o Can treatment begin before irreparable
damage done?

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12
Q

What are the first 4 steps in any therapy?

A

i) Correct diagnosis of disorder
ii) Identifying cause & mechanism of problem
iii) Rational design to replace/compensate problem
iv) this can only be done at a genetic level if nature of mutation understood

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13
Q

What are the 2 complex disease-causing mechanisms?

A
  • Unstable repeats, dominant disorders

- Unstable non-coding regions

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14
Q

Unstable repeats, dominant disorders

A
  • Repeat expansion, unstable, show anticipation
  • Disease onset earlier & more severe w each gen.

e. g. Huntington’s Disease
- Normal <36 CAG repeats
- -> 36-39 repeats = reduced penetrance, risk to offspring
- -> >40 repeats = affected

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15
Q

Unstable non-coding regions

A

-e.g. Fragile X mental retardation

<23 CGG repeats = intellectual disability, stable
26-50 repeats = normal & stable
50-58 = intermediate
59-200 = Fragile X premutation syndrome, unstable
>200 repeats = Fragile X mental retardation syndrome

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16
Q

What is the CRISPR-Cas system?

A

A prokaryotic immune system that confers resistance to plasmids and phages

17
Q

CRISPRs

  • abbreviation
  • characteristics
A

= clustered regularly interspacced short palindromic repeats

  • DNA loci containing short repeats
  • Each repetition followed by short segments of “spacer DNA” from previous exposure to virus
  • CRISPR spacers recognise & silence exogenous genetic elements in a similar manner to RNAi in eukaryotic organisms
  • CRISPRs occur with cas genes that code for proteins related to CRISPRs
18
Q

What are CRISPR-Cas’s used for?

- Process

A

Used for gene editing (silencing, enhancing or changing specific genes) in eukaryocytes

–> insert plasmid/virus that contain cas gene and specifically designed guide RNAs

–>Cas 9 endonuclease forms complex w dsDNA and single guide RNA

–> Cas9:sgRNA binds PAM to generate R-loop in taget DNA for genesis of ds break in target DNA

19
Q

Define the molecular therapy transcription

A

The upregulation of a homologous (similar) gene to produce a functionally equivalent protein

20
Q

Define the molecular therapy Splicing (antisense oligonucleotides)

A
  • Alter mRNA splicing to remove selected exons to bypass or overcome the mutation or alter splice isoforms
21
Q

Define the molecular therapy Translation (antisense oligonucleotides)

A

Transcript degradation - prevent translation RNase H, RNAi

- Translation initiation inhibition

22
Q

What are Antisense Therapies?

A
  • antisense transcripts occur naturally
  • synthetic antisense oligonucleotides (AO) used to:
    o Alter mRNA splicing e.g. induce exon skipping
    o Degrade transcripts
    o Block translation
23
Q

What are Target Splice Sites?

A
  • Alter splicing patterns using AOs to induce ‘exon skipping’

(this is only useful if reading frame is maintained/restored and if the shortened product in functional)

  • used to o Treat DMD
    o Correct aberrant splicing
    o Alter isoforms
24
Q

What is gene knockdown?

A
  • Antisense translational blockade

- Antisense seq. (25 bases long) targeted near translational site (ATG) are able to block translation

25
Q

Define translational blockade

A
  • down-regulated expression of genes that have negative effects
    o bird flu
    o Ebola virus
    o Hepatitis C

** sequence is effective against 75% human viruses

26
Q

What is RNase H?

A

= DNA antisense oligonucleotide annealed to an RNA strand inducing cellular RNaseH degradation of target RNA

27
Q

What is BMD?

- Characteristics

A

Becker’s Muscular Dystrophy

  • Milder allelic disorder than DMD
  • 1/30-50 000
  • In-frame deletions - dystrophin lvls >3% normal
  • variable phenotype
  • patients have dystrophin of variable quality/quantity
28
Q

What are MDs?

A

= Multisystem Disorders

  • All kinds of muscle
    Central NS
    Endocrine system
29
Q

What are the two isoforms of DMD & associated organs/tissue?

A

Long isoforms: skeletal, cardiac & smooth muscle, brain

Smaller isoforms: CNS, retine, kidneys

30
Q

Function of oligodeoxynucleotides (ODNs)?

A

Downregulate expression (RNaseH)

31
Q

Function of RNAi?

A

Transcript degradation

32
Q

Function of Modified RNA-AOs?

A
  • exon selection
  • non-productive splicing
  • translational blockade
  • isoform selection
  • exon inclusion
33
Q

What is SMA?

A

= Spinal Muscular Atrophy

  • Caused by loss of SMN1 on Chr5
  • Avg sized gene (8 exons, 30kb)
  • Important in ALL cells
  • loss of SMN1 = incompatible w life
  • SMN2 copy no. influences severity

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