Trinucleotide repeat expansion
Each of these processes involves a DNA synthesis step in which strand slippage might occur leading to trinucleotide repeat expansion.
However, from the eyes of geneticists, this relationship was disregarded and attributed to ascertainment bias; because of this, it took almost 200 years for a link between onset of disease and trinucleotide repeats (TNR) to be acknowledged.
Because of these discoveries, ideas involving anticipation in disease began to develop, and curiosity formed about how the causes could be related to TNRs.
[16][17] Detection of TNRs was made difficult by limited technology and methods early on, and years passed before the development of sufficient ways to measure the repeats.
[24] This slippage allows for the strand to find a stable intermediate amongst itself through base pairing, forming a secondary structure other than a duplex.
CAG and GCN repeats, which lead to polyglutamine and polyalanine tracts respectively, are normally found in the coding regions.
[25] At the 5' untranslated region, CGG and CAG repeats are found and responsible for fragile X syndrome and spinocerebellar ataxia 12.
After the hairpin forms, the primer realigns with the 3' end of the newly synthesized strand and continues the synthesis, leading to triplet repeat expansion.
It was found that diseases associated with trinucleotide repeat expansions contained secondary structures with hairpins, triplexes, and slipped-strand duplexes.
Research suggests that there is a direct, important correlation between the sex of the parent that transmits the mutation and the degree and phenotype of disorder in the child.,[32][33] The degree of repeat expansion and whether or not an expansion will occur has been directly linked to the sex of the transmitting parent in both non-coding and coding trinucleotide repeat disorders.
[32] One proposed but highly unlikely mechanism that plays a role in trinucleotide expansion transmission occurs during meiotic or mitotic recombination.
[32] In addition to this possibility of trinucleotide repeat expansion changes occurring due to slippage of Okazaki fragments, the ability of CG-rich trinucleotide repeat expansion sequences to form a special hairpin, toroid, and triplex DNA structures contributes to this model, suggesting error occurs during DNA replication.
When the repair process finishes for either mechanism, the length of the expansion is equivalent to the number of triplet repeats involved in the formation of the hairpin intermediate.
[27] A different mechanism, based on break-induced replication, has been proposed for large scale CAG repeats and can also occur in non-dividing cells.
[35] Some treatments for these symptoms seen in individuals with Fragile X syndrome include SSRI's, antipsychotic medications, stimulants, folic acid, and mood stabilizers.
[36] Fragile X syndrome men possess alleles in the full mutation range (>200 repeats) with FMRP protein levels much lower than normal and experience hypermethylation of the promoter region of the FMR1 gene.
[36] Huntington's disease (HD) is a dominantly, paternally transmitted neurological disorder that affects 1 in 15,000-20,000 people in many Western populations.
[38] HD involves the basal ganglia and the cerebral cortex and manifests as symptoms such as cognitive, motor, and/or psychiatric impairment.
[38] This autosomal dominant disorder results from the expansions of a trinucleotide repeat which involves CAG in exon 1 of the IT15 gene.
[39] The majority of all juvenile HD cases stem from the transmission of a high CAG trinucleotide repeat number that is a result of paternal gametogenesis.
[41] Individuals with Myotonic Dystrophy experience severe, debilitating physical symptoms such as muscle weakness, heartbeat issues, and difficulty breathing that can be improved through treatment to maximize patients' mobility and everyday activity to alleviate some stress of their caretakers.
[42] Research has shown that there is a direct correlation between expansion repeat number, IQ, and an individual's degree of visual-spatial impairment.
[42] Myotonic dystrophy results from a (CTG)n trinucleotide repeat expansion that resides in a 3' untranslated region of a serine/threonine kinase coding transcript.
[47][48] It has been proposed that the repeat expansion happens in the maternal oocyte during meiotic cell cycle arrest in prophase I, however the mechanism remains nebulous.
It is understood that as the DNA polymerase fails in this way, the resulting single-stranded loops left behind in the template strand undergo deletion, affecting TNR length.
[15] In Huntington's disease (HD), the exact timing has not been determined; however there are a number of proposed points during germ cell development at which expansion is thought to occur.
RNAi begins with RNase Dicer cleaving a 21-25 nucleotide long stand of double stranded RNA substrates into small fragments.
Despite the obvious benefits that antisense therapeutics can bring to the world with their ability to silence neural disease, there are many issues with the development of this therapy.
This results in a high amount of chemical modification when altering the chemistry to allow for the nucleases to surpass the degradation of these synthetic nucleic acids.
Native ASOs have a very short half-life even before being filtered throughout the body especially in the kidney and with the a high negative charge makes the crossing through the vascular system or membranes very difficult when trying to reach the targeted DNA or mRNA strands.
