Huntingtin gene (HTT) genomic DNA (5' UTR, exon 1, and intron 1) (HTT genomic DNA)

The Huntingtin (HTT) gene genomic DNA, specifically the 5' untranslated region (UTR), exon 1, and intron 1, is the primary locus involved in the pathogenesis of Huntington's disease (HD) (NCBI Gene, 2024). Exon 1 contains a polymorphic CAG trinucleotide repeat that, when expanded beyond 35 units, leads to the synthesis of a mutant huntingtin (mHTT) protein with an elongated polyglutamine tract (Tabrizi et al., NEJM, 2019). This mutation results in toxic gain-of-function and loss of normal protein function, causing progressive neurodegeneration in the striatum and cortex (Saudou & Humbert, Neuron, 2016). Therapeutic interventions targeting these genomic regions aim to reduce mHTT levels at the source through gene editing (e.g., CRISPR/Cas9), transcriptional repression, or modulation of pre-mRNA splicing (Yang et al., Cell, 2017). A significant challenge in targeting this region is the need for allele-specific approaches that selectively silence the mutant allele while sparing the wild-type allele, which is vital for neuronal health and development (Zuccato et al., Physiological Reviews, 2010). Current clinical efforts include antisense oligonucleotides and gene therapies designed to bind to or interfere with the transcription and processing of this specific genomic sequence (Wild & Tabrizi, Lancet Neurology, 2017).

Other names

HTTIT15HD geneHuntington disease gene locusHuntingtin 5' regionHTT exon 1

Mechanism of action involves the use of gene editing tools to permanently modify the DNA sequence, or the use of antisense oligonucleotides and small molecules to interfere with the transcription and splicing of the pre-mRNA derived from this genomic region, thereby reducing the production of toxic mutant huntingtin protein (Wild & Tabrizi, Lancet Neurology, 2017).