Huntingtin gene (HTT) CAG repeat expansion (HTT CAG repeat)

The Huntingtin (HTT) gene CAG repeat expansion is the causative genetic mutation for Huntington's disease (HD), an autosomal dominant neurodegenerative disorder (NCBI Gene ID: 3064). In healthy individuals, the HTT gene typically contains 6 to 35 CAG repeats; however, an expansion beyond 36 repeats leads to the production of a mutant huntingtin (mHTT) protein containing an elongated polyglutamine (polyQ) tract (UniProt: P42858). This mutant protein is prone to misfolding and aggregation, which triggers a cascade of cellular dysfunction including transcriptional dysregulation, impaired axonal transport, and mitochondrial failure, ultimately leading to neuronal death in the striatum and cortex (PubMed: 29035358). Therapeutic strategies targeting this expansion, often referred to as huntingtin-lowering therapies, utilize antisense oligonucleotides (ASOs), RNA interference (RNAi), and small molecule splicing modulators to reduce the expression of the toxic mHTT protein (PubMed: 31067372). A critical challenge in drug development is achieving allele-specific silencing to preserve the essential biological functions of the wild-type HTT protein while effectively neutralizing the mutant form (PubMed: 33536539). Monitoring of these therapies typically involves measuring mHTT levels in the cerebrospinal fluid and tracking neurodegenerative biomarkers like neurofilament light chain (NfL).

Other names

HTTIT15Huntington disease geneCAG trinucleotide repeatHD geneInteresting Transcript 15

Antisense oligonucleotide-mediated mRNA degradation, RNA interference (RNAi) via microRNA or siRNA, small molecule-mediated splicing modulation to induce premature stop codons, and CRISPR-based gene editing to excise or disrupt the expanded repeat.