Huntingtin messenger RNA CAG repeat tract

The Huntingtin (HTT) mRNA CAG repeat tract is a sequence of trinucleotide repeats located in the first exon of the HTT gene transcript (Source: UniProt P42858). In healthy individuals, this tract typically contains fewer than 35 repeats, but expansions beyond 36 repeats cause Huntington's disease (HD), a progressive and fatal neurodegenerative disorder (PMID: 31034602). The expanded mRNA tract serves as a template for the translation of mutant huntingtin (mHTT) protein, which contains an elongated polyglutamine (polyQ) domain that leads to protein misfolding, aggregation, and neuronal toxicity (PMID: 29463760). Beyond its role in protein synthesis, the expanded CAG repeats can form stable RNA secondary structures, such as hairpins, that sequester essential RNA-binding proteins and contribute to cellular dysfunction (PMID: 31570881). This tract is a primary target for therapeutic interventions, including antisense oligonucleotides (ASOs) like Tominersen and RNA interference (RNAi) agents like AMT-130, which aim to reduce mHTT levels by promoting the degradation of the HTT transcript (PMID: 33789084). Small molecules such as PTC518 also target the HTT mRNA by modulating its splicing to induce premature termination and lower protein expression (Source: PTC Therapeutics). A major challenge in targeting this tract is achieving allele-selectivity to avoid suppressing the wild-type HTT protein, which is essential for normal cellular functions (PMID: 31570881).

Other names

HTT CAG expansionmHTT mRNA CAG repeatHuntingtin exon 1 CAG tractHTT polyglutamine tract (mRNA)

RNase H-mediated degradation of mRNA, RNA interference (RNAi), and splicing modulation to reduce the expression of mutant huntingtin protein.