Genetics (Day 2) Flashcards
What trinucleotide repeat disorder leads to a loss of protein (null mutations)?
- Fragile X Syndrome (FRAXA)
- Friedreich Ataxia (FRDA)
What trinucleotide repeat disorders lead to altered RNA function (gain of function)?
- Myotonic Dystrophy I (DM1)
- Fragile X Associated Tremor/Ataxia Syndrome (FXTAS)
Where is the location of the Friedreich Ataxia repeat?
Intron 1
Where is the location of the Myotonic Dystrophy disease repeat?
3’UTR
Do not cause disease but have meiotic instability (sex specific).
Mutable (Premutation) alleles
Pathogenic in some individuals, milder presentation, late onset, and meiotic instability.
Reduced Penetrance Alleles
Associated with disease with full penetrance. Show meiotic instability and for some diseases, also have mitotic instability.
Disease Alleles
What is the trinucleotide repeat for Fragile X Syndrome and FXTAS?
CGG
What is the trinucleotide repeat for Friedreich Ataxia?
GAA
What is the trinucleotide repeat for Huntington and SCA?
CAG
What is the trinucleotide repeat Myotonic Dystrophy?
CTG
What diseases have a paternal expansion bias?
Most CAG expansions (poly Glutamine) like:
- Huntington Disease
- Spinocerebellar Ataxias (SCA)
What diseases have a maternal expansion bias?
- Fragile X (FRAXA)
- Myotonic Dystrophy (DM1)
- Friedreich Ataxia (FRDA)
How would one measure repeat expansions?
- PCR/Gel Electrophoresis: Moderate expansions (Huntington, SCA)
- Southern Blotting: Large expansions (Fragile X, Myotonic Dystrophy, Friedrich Ataxia)
- Western Blotting: Absence of protein
What trinucleotide repeat disorders lead to altered protein function (gain of function)?
- Huntington Disease
- Spinocerebellar Ataxias (SCA)
Where is the location of the Huntington Disease repeat?
Exon 1
Where is the location of the SCA1 disease repeat?
Exon 8
Where is the location of the Fragile X (Site A) repeat?
5’UTR
What are the multiple pathogenic mechanisms in polyQ diseases?
- Proteolytic cleavage with toxic fragments
- Proteasome impairment
- Aggregate formation
- Mitochondrial dysfunction
- Transcription dysregulation
- RNA toxicity
Stably transmitted to offspring and retained in somatic tissues through developement.
Static Mutations
May continue to mutate during transmission to offspring and during tissue development.
Dynamic Mutations
Most dynamic mutations are due to?
Trinucleotide or Triplet Repeat Disorders
Backward slipping dynamic mutations lead to?
Repeat expansions (insertions)
Forward slipping dynamic mutations lead to?
Repeat contractions (deletions)
