Triplet Repeats LOH - Friedreich Ataxia Flashcards
what are triplet repeat disorders
disorders caused by expansions of triplet nucleotide repeat sequences that are polymorphic in the population
what is anticipation?
The tendency for the severity of a condition to increase in successive generations. Also earlier age of onset.
What are dynamic mutations
An unstable expande repeat that changes in size (increases or decreases) on transmission between parent and child.
What are the different mechanisms of triplet repeat disorders?
LOF - reduced or absence of gene product or its function (FraX, Friedreich).
GOF - eg CAG repeat expansions polyglutamine aggregates causing HD or SCAs.
What triplet repeat disorders have their repeat tract within the coding region?
HD - CAG, SCA and SBMA.
What triplet repeat disorders have their repeat tract within the non-coding region?
FraX 5’UTR, DM 3’UTR, Friedreich’s within intron 1.
What are the clinical features of Friedreich Ataxia?
Progressive ataxia mean age of onset 10-15yrs. Muscle weakness; cardioymyopathy (2/3rd), dysarthia (slowing, slurred speech), gait, limb and truncal ataxia.
What percentage have atypical Friedriech’s?
25% late onset
What mode of inheritance if Friedriech ataxia?
AR
What is the pathology of Friedrich ataxia?
Expansion results in defective transcription of the FXN gene leading to deficiency of frataxin. The FRDA phenotype is due to a deficiency of FXN mRNA and frataxin protein (loss of function), caused by defects in transcription (initiation and elongation) and epigenetic changes (histone deacetylation, methylation). Formation of R loops on expanded GAA/CGG alleles act as the primary trigger for repression of expanded FXN and FRMR1 alleles, which in turn promote heterochromatin formation. Reduced expression is associated with an increase in H3K9 methylation and decreased H3K9 acetylation.
FXN transcription is inhibited by the formation of non-B DNA structures, such as triplexes and sticky DNA (expanded GAA alleles), which physically block the transcriptional machinery proceeding along the DNA template (elongation). DNA-RNA hybrid structures form and impede FXN transcription. RNA-DNA hybrids are formed when the nascent RNA hybridises to the DNA template behind the elongating RNA pol II. These are termed ‘R-loops’ and are formed over GAA (FRDA) and CGG (FRAX) repeats, possibly creating a roadblock for RNA pol II and interfering with transcriptional elongation by promoting RNA pol II termination.
What is the function of Frataxin protein?
Nuclear incoded small mitochondrial protein. FRDA shares characteristics with classic mitochondrial disorders MELAS and MERFF suggesting the pathology of FRDA is a result of oxidative damage. FRDA functions in iron homeostasis. Synthises biogenenesis of iron-sulphur clusters (ISCs), iron-trafficking in mitochondria, and as an iron chaperone (delivers iron to ferrochelatase for the introduction into porphyrin in heme biosynthesis). Since several complexes of the respiratory chain contain iron-sulfur clusters, frataxin has a direct impact on mitochondrial function and respiration.d for the synthesis of iron-sulphur clusters, and thereby, for the synthesis of enzymes in the respiratory chain. Loss of frataxin abrogates iron-sulfur cluster synthesis and assembly, decreasing the activity of enzymes dependent on them, and leading to iron accumulation in the mitochondria. This negatively impacts mitochondria-rich tissues including heart cardiomyocytes and neuronal cells in the central and peripheral nervous system.
What % of Friedriech have a an expansion?
98% an 2% have expansion and PM/deletion on other allele.
What are the size ranges for Friedriech GAA repeats?
Normal 5-33 Premutation 34-65 Borderline - 44-66 full 66-1700 Shortest allele to expand is 44. ▪ 80-85% <12 repeats (small normal; SN) ▪ 15% 12-33 repeats (large normal; LN)
What parent is transmission associated with contractions in Friedriech ataxia?
maternal transmission is associated with expansions and contractions; paternal transmission is associated primarily, but not exclusively, with contractions. There is a strong contraction bias among longer expansions (>500 repeats).
Is there a genotype-phenotype correlation in Friedreich ataxia?
Shorter GAA expansion sizes are associated with later age of onset and less severe phenotype and slower disease progression
