Trinucleotide Repeat Expansion Flashcards
Why do trinucleotide repeats (TNRs) expand?
Unknown mechanism. Hallmark is Instability
What are 4 principals associated with TNR disorders?
- Molecular characteristics and consequences of expansion differ.
- Tendency for repeat expansions depends on transmitting parent
- Those with abnormal number of TNRs who have no/fewer symptoms carry “pre-mutations”
- TNR display genetic anticipation
What are the 2 TNR polyglutamine diseases that occur in coding region of gene? What is disease presentation caused by?
- Huntington’s
- Spinocerebellar ataxia
(Caused by excess glutamine insertions in the protein)
How is TNR expansion in the Non-coding region of the gene pathogenic?
Disease caused by diminished or absent target protein or ‘RNA toxicity’
What is genetic anticipation?
With TNR expansion, the more repeats the more severe and early the onset of disease is.
This is different from typical mendelian genetics where expression is constant thru generations (apart from penetrance/phenotypic variability)
What are some hallmark clinical progressions seen in pts w/ Huntingtons?
Saccadic extraocular eye movements: (these slow movements that are kind of like brief off center shifts of the eyes)
Ataxic Gait: poor stability and balance. Need a wide legged stance for balance and walking in tandem is difficult. Torso is also very unsteady
Choreatic movements: spontaneous non-patterned involuntary movements of muscles.
What is the inheritence pattern of Huntington’s?
Autosomal dominant (progressive neurodegenerative disorder)
Where does the increased repeats occur in HD? What is the pattern of repeats?
Glutamines(CAG)
1st exon in huntington protein.
Where is huntington protein typically located? Where is it pathogenic?
Huntington protein expressed in brain and large number of body tissues
Pathology is restricted to CNS
is not a knock out of huntingtin, accumulation of these malshaped proteins
Aggregates -> Modify transcription Induce proteolysis Interfere with axonal transport Disrupt synaptic transmission
What is incidence of HD? Onset? Clinical features?
3-7/100,000
Onset is midlife with duration of 15-20years.
Features:
Involuntary choreiform movements
Cognitive impairment
Mood disorders and behavioral changes
How many repeats are seen in HDwt? HDintermediate? HDpremut? HDmt?
What is the difference between them?
HDwt - 6-26 CAG repeats
HDint - 27-35 repeats => unstable, usually no disease, prone to repeating more
HDpremut - 36-39 repeats => may be incomplete penetrance (either +/- for disease, no alternative phenotype seen like in other TNRs)
HDmut - >39 repeats - pt is always affected.
How does repeat expansion continue to expand in HD?
Spermatogenesis (thru the dad)
Mom can still have/transmit the diz, but if she is just a carrier (int/premut) then she won’t give the kids anymore repeats
How can we diagnose HD?
Thru PCR.
TNR increases the size of the PCR product.
We would see heavier bands in pts with more repeats.
What is the most common inherited cause of intellectual disability and autism spectrum disorders?
Fragile X syndrome.
(Remember trisomy 21s (Down syndrome) are the most common chromosomal cause of developmental delays. But those arent all caused by inheritance.)
What is the inheritance pattern of Fragile X syndrome?
X-linked (hard to tell dominant vs recessive)
What and where is the TNR in FXS?
CGG expansion at promoter of the fragile X mental retardation gene (FMR1)
5’UTR
T/F FMR1 gene is only seen in mammals?
False, highly conserved across species
What is FMR1wt repeat #? FRM1premut? FMR1mutation?
FMR1wt - 6-44 repeats (does not expand)
FMR1premut - 55-200 CGG repeats
FMR1mutation - >200-4000 CGG repeats
T/F: In fragile X syndrome there is more risk for expansion when transmitted by males?
False; females.
What does the FMR protein do?
RNA-binding protein: Translational regulator for the target mRNAs.
Important in axonal transport/ generation of dendrites
Arrests development of neurons
How does expansion >200 repeats in FXS manifest?
Full mutation: full transcriptional silencing of FMR1 gene. Promoter becomes methylated. Full cognitive disability
Affected males (w/ full mutation): Cognitive disability (low IQ) Post puberty changed: large narrow facew, large ears, hypotonia, macroochidism (large testes) - 90% of males
How does an expansion of 55-200 repeats manifest in FXS?
Prevelence more common in females than males (for premutation)
Tremor-Ataxia Syndrome (FXS associated):
Risk males>females
Progressive neurodegenerative (cognitive decline in elderly)
Primary Ovarian Insufficiency:
Cessation of menses before 40yo
20% female with pre-mutation (1% in general population)
What is hallmark premutation phenotype of FXS in females? How does it occur?
Primary Ovarian Insufficiency.
Enlarged promoter region in FMRgene leads to other binding proteins being sequestered (that were originally on other transcripts). Disrupt other factors function.
What kind of atypical transmission patterns do we see in FXS?
Carrier males: 20% who carry FMR1premut (20-200 repeats) are clinically normal
Affected females:
30-50% carrier females with full mutation are affected
-due to selective S inactivation
What is inheritance pattern of Friedreich’s ataxia?
Autosomal recessive disorder caused by GAA expansion at 1st intron of Frataxin gene (FRDA)
How many cases of hereditary ataxia does FA account for?
50%
What is repeat for FRDAwt? FRDAmut?
Normal : GAA 7-34 repeats
FA: 200-1200 GAA repeats
What does TNR lead to in the Frataxin gene?
MRNA transcript loss
How does FA influence mRNA transcript loss?
MRNA loses ability to splice correctly. Intron left in and mRNA broken down rapidly
What kind of protein is Frataxin?
Mitochondrial
May have something to do with iron/oxidative stress
Where is expression of frataxin the highest?
Heart and spinal cord (pancreas too)
Selective cell loss-> neurological dysfunction, cardiomyopathy, DM type 1
What is inheritance pathway for Myotonic Dystrophy (type1)?
Autosomal dominant with expansion of CTG in 3’UTR of the dystrophia myotonia protein kinase (DMPK)
What is the most common cause of adult onset nuscular dystrophy?
Type 1 MD
1/10,000
What is repeat number for wt, premutation, mutation?
DMPKwt= 5-34 CTG alleles
DMPKpremut= 35-49 CTG repeats w/o clinical phenotype
DMPKmutation = >50 repeats, into the thousands
In MD1, is there phenotypic expression of premutation gene?
No
What are the phenotypic expression of MD1 in relation to repeat #?
MILD (late onset) = 50-150
Cataracts, mild myotonia
Classic MD1 (150-1000) Muscle wasting weakness, myotonia, balding, cardiac conduction deficits
Severe/congenital (>1000): infantile hypotonia, resp dysfunction.
How can males and females differ in their transmission of MD1?
Males - transmit repeats up to 1000
Females- may transmit thousands of repeats!
How does MD1 manifest disease?
RNA-mediated toxicity
Alternative splicing that should occur may not occur due to recruitment of binding proteins attached to newly formed hairpin loop.
