Created by Ellie Quinn
over 10 years ago
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Trinucleotide repeats are preferentially selected as they don't cause a frameshift Triplet repeats can cause various RNA structures: Quadruplex Stable Hairpin e.g. CAG Semi-stable hairpin Single stranded Trinucleotide repeat disorders are dynamicThe triplet repeat can expand or contractExpansion is affected by: Threshold - Repeat size - the larger the repeat size, the larger the expansion is likely to be on transmission Parent of Origin Flanking/Interrupting repeats - any nucleotides flanking the repeat sequence or within the repeat sequence will alter the secondary structure, and so potential to expand is altered (fragile x syndrome?) Anticipation - tendency for age of onset to decrease and severity of symptoms to increase through successive generations with a trinucleotide repeat disorderMechanism of instability "Slippage" during DNA replication Looped intermediates are formed which become incorporated into the DNA Pathogenic Mechanism Loss of function of protein - e.g. Fragile X Syndrome Gain of function mutation - e.g. Huntington's (protein level) or Fragile-X Associated Tremor (FXTAS) (RNA level) Post-translation modification - e.g. Polyglutamine disorders Autophagy - degradation of misfolded proteins
Friedrich's Ataxia Autosomal recessive Typically expanded GAA repeat in the first intron of FXN gene This induces a heterochromatin rather than euchromatin structure -> less transcription Less production of the protein frataxin Normally, frataxin regulates iron levels in the mitochondria If there is reduced concentration - build up of iron in mitochondria causes oxidative stress Oxygen based free radicals build up, damaging the mitochondria Work to find drug that can upregulate FXN expression by reversing heterochromatinisation nictotinamide has shown to be effective - currently in phase II clinical trials Clinical Presentation Affects 1 in 50,000 in the US Symptoms usually present between 5 to 15 years Muscle weakness in arms and legs Loss of coordination Slurred speech Visual impairment Scoliosis Diabetes Heart problems Median age of death 35 years
Huntington's Disease IT15 (huntingtin) gene codes for the huntingtin protein Modest expansion of CAG repeats in the coding region (40-100bps) Extended polyglutamine repeat causes abnormal folding (CAG codes for glutamine) Mutant protein aggregates as toxic polyQ protein in neuronal cells of basal ganglia and cortex Clinical Presentation May begin with subtle mood and cognition disturbances Later develop chorea (repetitive movements) lack of muscle control Psychiatric problems - apathy, depression
Myotonic Dystrophy Most common muscle dystrophy in adults 3-15 per 100,000 in Europe Autosomal dominant Progressive myopathy, myotonia and multi-organ involvement Two kinds: DM1 and DM2 DM1 - severe - caused by CTG expansion in 3'-UTR of DMPK DM2 - mild - cause by CCTG expansion in CNBP
Fragile X Fragile site/break just above the tip of the long arm of the X chromosome FMR1 gene codes for Fragile X Mental Retardation Protein (FMRP) If there is an expansion >200 repeats, methylation occurs which causes the DNA around the gene to become heterochromatin, inhibiting translation Lack of FMRP leads to excessive production of dendritic proteins Thus, dysregulation of glutaminergic signalling This leads to reduced neuronal plasticity - consequences are learning and memory deficits & social problems, including social anxiety Expansion Normally CGG repeats can expand through male and female transmission BUT when near the threshold - ie. when individual has a premutation expansion only occurs during female transmission Normally, every 100 CGG repeats, there is an AGG repeat which helps anchor the DNA Expansion can disrupt this anchoring Fragile X Associated Tremor (FTAX)Caused by abnormal mRNA gain of function
Intro
Friedrich's Ataxia
Huntington's Disease
Myotonic Dystrophy
Fragile X
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