Mutant huntingtin pre-messenger RNA (mutant HTT pre-mRNA)

Mutant huntingtin pre-messenger RNA (pre-mRNA) is the direct RNA transcript produced from the mutant huntingtin (HTT) gene, which contains an expanded CAG trinucleotide repeat characteristic of Huntington's disease (HD)[4][8]. This pre-mRNA undergoes alternative splicing, polyadenylation, and other post-transcriptional modifications, and serves as the template for the production of the pathogenic mutant huntingtin protein (mHTT). Beyond encoding the toxic protein, mutant HTT pre-mRNA itself contributes to HD pathology via toxic RNA-mediated effects, including aberrant splicing leading to toxic exon 1 fragment production, misregulation of RNA binding proteins, abnormal nuclear clustering, and dysregulation of RNA processing mechanisms[1][4][5][8]. Therapeutic strategies increasingly target this pre-mRNA directly in an attempt to lower pathogenic protein expression or modulate abnormal RNA processing, highlighting its importance as a disease-modifying therapeutic target[2][4][9].

Other names

mutant HTT pre-mRNAmHTT pre-mRNAmutant huntingtin RNAmutant HTT transcript

Splicing modifiers induce inclusion of a poison exon leading to nonsense-mediated decay and reduction of toxic mutant HTT protein[2][9] Antisense oligonucleotides bind to mHTT pre-mRNA and promote its degradation or alter its splicing to reduce protein levels[4][8] Targeted modulation of m6A RNA modification to influence aberrant splicing and decrease mutant transcripts[1]