Browse the corpus

Trinucleotide repeats are sets of three nucleotides present in succession in various copy numbers throughout the human genome.[1] These areas of the genome are unstable and polymorphic.[2] Trinucleotide repeat disorders are a series of conditions caused by triplets in a mutated gene that are present in greater number than found in normal genetic sequencing.[3] These abnormal sequences are known as "expansions" and present across many stages of human development and numerous cell types.[3] Repetitive sequences of genetic code are quite common. However, when these sequences grow beyond the scope of what would be considered normal, they cause disease. While the human genome has mechanisms to protect against these expansions, patients present with what can be severe neuromuscular and neurodegenerative disorders.[4] There have been many diseases discovered by TNR expansions, but the most prominent are spinocerebellar ataxia, Huntington disease, Fragile X syndrome, myotonic dystrophy, and Friedrich ataxia. These disorders, as well as the genetic and molecular development of these disorders, will be discussed below.

If trinucleotide repeats exist in exonic sequences, an increasing number of copies can have an effect on transcription and translation of proteins contributing to pathology. However, many also occur in UTRs, and, while it would appear not to affect pathology, they actually can still contribute to disease.[5] Trinucleotide repeats have been noted to be particularly unstable[2], causing increased copy numbers and pathology in those who are genetically predisposed. Most trinucleotide repeat disorders have a strong genetic basis and an extensive family history of the disease in multiple generations. Increasing copy numbers of the trinucleotide repeats can be seen in successive generations, resulting in an earlier disease onset than the previous generation, a phenomenon known as anticipation. The mechanism by which trinucleotide repeats cause disease is still under extensive study, but some theories have emerged about what contributes to trinucleotide repeat instability. One study points to mismatch repair (MMR) proteins and their role in promoting instability through overexpression.[1] MMR proteins are one of many essential DNA repair pathways in the cell to protect from mutations and the subsequent development of severe pathology. However, they have been shown to be mutagenic at high numbers as a result of overexpression, contributing to trinucleotide repeat expansion.[1][6] Base excision repair (BER) has also been shown to play a role in contributing to trinucleotide repeat instability, especially after successive repairs from base oxidation.[6] BER is the mechanism by which damaged bases are removed and replaced in the DNA to prevent mutations and DNA strand breaks. However, the mechanism is not always effective and can contribute to trinucleotide repeat expansions with multiple repair cycles.[6]