Mutant huntingtin mRNA (mHTT mRNA)

Mutant huntingtin messenger RNA (**mHTT mRNA**) is the transcribed product from a pathogenic allele of the human *huntingtin* (*HTT*) gene containing an expanded CAG trinucleotide repeat. This expansion results in a longer polyglutamine tract within the encoded protein, which causes Huntington’s disease—a fatal neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms. The *mHTT* transcript serves as a template for both full-length and aberrantly spliced forms that produce highly aggregation-prone N-terminal fragments such as exon 1 huntingtin. These fragments are central drivers of cellular toxicity through mechanisms including aggregate formation, mitochondrial dysfunction, impaired cargo trafficking in neurons, and dysregulation at multiple levels including alternative polyadenylation and epitranscriptomic modification (notably increased N6-methyladenosine [m^6A] methylation). Therapeutic strategies targeting *mHTT* mRNA aim to lower its abundance using antisense oligonucleotides or gene therapies based on microRNAs/RNAi delivered by viral vectors; these approaches have shown promise in preclinical models and early clinical trials by reducing both full-length and toxic truncated proteins derived from this transcript. Safety concerns include potential adverse effects from lowering normal *huntingtin*, off-target silencing, immune activation against therapeutic agents, and incomplete suppression due to alternative splicing events.

Other names

mutant HTT mRNAmutant huntingtin transcriptexpanded CAG HTT mRNAHD-causing HTT mRNA

Reduction of mutant huntingtin protein synthesis by degrading or blocking translation of the pathogenic mHTT transcript; Modulation of aberrant splicing to reduce toxic exon 1 fragment production; Inhibition of polyQ expansion-driven aggregation at the RNA level