Huntingtin gene (HTT) with expanded CAG repeats (mHTT)

The huntingtin gene (HTT) contains a polymorphic CAG trinucleotide repeat in its first exon (MedlinePlus, 2023). In healthy individuals, this repeat typically ranges from 6 to 35 units; however, an expansion to 36 or more repeats leads to the production of a mutant huntingtin (mHTT) protein with an abnormally long polyglutamine tract (NIH, 2022). This expansion causes the protein to misfold and aggregate, leading to progressive neurodegeneration, particularly in the striatum and cortex (UniProt, 2024). As the genetic cause of Huntington's disease, the mutant HTT gene and its mRNA transcript are primary targets for therapeutic intervention (Nature Reviews Drug Discovery, 2019). Current strategies focus on lowering mHTT levels using antisense oligonucleotides (ASOs) like Tominersen, RNA interference (RNAi) like AMT-130, and small molecule splicing modulators like PTC518 (ClinicalTrials.gov, 2024). Some approaches aim for allele-specific silencing to preserve the essential functions of the wild-type HTT protein, while others utilize non-selective silencing (Wave Life Sciences, 2024). Emerging technologies like CRISPR/Cas9 are also being explored to permanently correct or disrupt the expanded CAG repeat at the genomic level (PubMed, 2023).

Other names

HTTHD geneIT15Interesting Transcript 15Huntington disease gene

Antisense oligonucleotide-mediated RNA degradation, RNA interference (RNAi), small molecule-mediated splicing modulation, and gene editing (CRISPR/Cas9).