Trinucleotide Repeat Disorders Flashcards
examples of trinucleotide repeat disorders
- fragile x
- friedreich’s ataxia
- huntington’s disease
- mytonic dystrophy
mechanism of trinucleotide repeat disorder
- expansion of number of repeats
* likely due to slipped DNA mispairing
unstable repeat expansions
- number of repeats may increase in offspring
* key: genetic abnormality changes over time
anticipation
- phenomenon where disease severity worse in subsequent generations with earlier onset
- due to more repeats accumulating in abnormal gene
fragile x inheritance
x linked dominant
gene involved in fragile x
- FMR1 gene = fragile x mental retardation 1
* q arm of x chromosome
increase in CGG repeats in fragile x leads to
DNA methylation of FMR1 gene -> silencing
2nd most common cause of intellectual disability
fragile x (down syndrome 1st)
common features in fragile x
- long narrow face
- large ears
- large jaw
- macroorchidism (after puberty)
- CT findings (joint laxity)
associated mental problems with fragile x
- anxiety
- ADHD
- often features of autism
- OCD
- aggression
- depression
friedreich’s ataxia inheritance
autosomal recessive
friedreich’s ataxia gene
- frataxin (FXN) gene on chromosome 9
* needed for mitochondrial function
increased GAA repeats in freidreich’s ataxia causes
decreased frataxin levels -> mitochondrial dystunction
frataxin protein
- mitochondrial protein
- high levels in brain, heart, pancreas
- abnormal -> mitochondrial dysfunction
presentation of friedreich’s ataxia
- typical onset 5-15 yo
* cerebellar and spinal cord degeneration -> loss of balance and weakness
physical deformities that commonly develop in friedreich’s ataxia
- kyphoscoliosis
* foot abnormalities (pes cavus)
common problem associated with friedreich’s ataxia
- hypertrophic cardiomyopathy
- a-fib -> tachycardia
- diabetes
huntington’s disease inheritance
autosomal dominant
gene and location in huntington’s disease
- HTT gene located at 4P16.3
* codes for protein huntington
what does CAG expansion cause in huntington disease
- CAG codes for glutamine
* polyglutamine disorder
cause of symptoms in huntingtons disease
- degeneration in basal ganglia (striatum)
- leads to dementia, chorea, ataxia, dysarthria (difficulty with formation of speech)
- death usually 10-20 years after diagnosis
myotonic dystrophy inheritance
autosomal dominant
type 1 myotonic dystrophy gene
- DMPK gene on chromosome 19
- codes for myotonic dystrophy protein kinase
- abnormal gene transcribed to mRNA but not translated
presentation of myotonic dystrophy
- most commonly begins in adulthood (20-30yo)
- progressive muscle wasting/weakness
- myotonia (prolonged muscle contractions)
- unable to relax muscle after use
- cannot release grip
- locking of jaw
facial characteristics in myotonic dystrophy
- facial muscles often affected -> weakness/wasting->
* long narrow face and hollowed cheeks
other problems found in myotonic dystrophy
- multisystem disorder:
- hypogonadism
- cataracts
- cardiac arrhythmia
- frontal balding
- insulin resistance
- arrhythmias (atrial flutter and fibrillation)
- 1st degree AV vlock
- bundle branch block
- respiratory complications
- intellectual disability (worse with earlier onset)
where can trinucleotide repeat expansions occur
•coding or non-coding regions of gene (anywhere in gene)
causes of trinucleotide repeat expansions
•gene conversion (unequal crossing over) during meiosis
OR
mistakes in:
•DNA replication
•double-stranded DNA break repair
•base excision repair of oxidative damage
•single-stranded DNA gap repair
where would you find high expression of huntington protein
testes and brain
function of huntington protein
- found in nucleus and cytoplasm
- regulates intracellular transport of many proteins
- shuttles transcription factors in and out of nucleus
- may sequester TFs
- required for normal embryonic devand neurogenesis
Expansion of CAG region in huntington disease results in
aggregation of the mutant protein into inclusion bodies
where does the CAG repeat expansion occur in huntingtons disease
exon I
hypothesis of expansion mechanism in huntington disease
meiotic instability in sperm -> unequal crossing over
common differential diagnosis in patient with suspicion for fragile x
- down syndrome
- williams syndrome
- angelman
- autism spectrum disorer
location of trinucleotide repeat expansion in fragile x
- near the promoter in 5’ UTR of FMR-1 gene, which encodes FMRP
- silences the promoter
FMRP implicated in
- dendritic spine maturation
- synapse formation
- synaptic plasticity
associated problems with fragile x
- mitral valve prolapse
- HTN
- sz activity
- possible strabismus
- hypotonia
- pes planus
common symptoms of freidreich ataxia
- muscle weakness in arms/legs
- loss of coordination
- vision/hearing impairment
- slurred speech
- scoliosis
- pes cavus
spinal cord change in friedreich ataxia
- spinal cord becomes thinner
* nerves lose part of myelin sheath
what does frataxin protein do
•removes iron in the cytoplasm and around mitochondria
iron buildup in mutant frataxin protein
- causes free radical damage to mitochondrial membrane
- oxidative stress
- esp affects nerves and muscle cells
location of trinucleotide expansion in friedreichs ataxia
first intron on FXN gene -> transcriptional repression
compound heterozygotes in friedreichs ataxia
- 4% of patients
* have expansion in 1 allele and some other mutation of FXN in other allele
treatment of friedreichs ataxia
- supportive: scoliosis surgery if indicated, cardia meds, DM meds, PT
- genetic counseling:
- 25% recurrence risk (AR)
- carrier frequency is 1/110, affects 1/50,000 in US
location of trinucleotide repeat expansion in myotonic dystrophy
3’ intron
location of trinucleotide repeat expansion in huntington disease
exon 1
