| HTT — Huntingtin | |
|---|---|
| Symbol | HTT |
| Full Name | Huntingtin |
| Chromosome | 4p16.3 |
| NCBI Gene | 3064 |
| Ensembl | ENSG00000197393 |
| OMIM | 143100 |
| UniProt | P42858 |
| Protein Size | 3,144 amino acids (~350 kDa) |
| Disease | Huntington's Disease |
| Expression | Striatum (caudate/putamen), [Cortex](/brain-regions/cortex), [Hippocampus](/brain-regions/hippocampus), Cerebellum |
| Polyglutamine Repeat | |
| Normal: 10-35 repeats | Disease: ≥36 repeats | Juvenile: >60 repeats | |
HTT (Huntingtin) is a gene located on chromosome 4p16.3 that encodes the huntingtin (HTT) protein — a large, multi-functional protein central to Huntington's disease pathogenesis. The gene was identified in 1993 when the CAG trinucleotide repeat expansion responsible for HD was discovered[1]. Huntingtin is one of the largest proteins in the human proteome at 3,144 amino acids (~350 kDa) and performs essential functions in neurons including intracellular transport, gene transcription regulation, synaptic function, and cell survival[2].
The discovery that a CAG repeat expansion in HTT causes HD revealed the fundamental mechanism of polyglutamine disorders. HD is autosomal dominant — each child of an affected parent has a 50% chance of inheriting the mutant allele. The number of CAG repeats determines age of onset, with longer expansions causing earlier disease manifestation[3].
Huntington's disease is caused by an autosomal dominant CAG trinucleotide repeat expansion in the first exon of HTT[1:1][4]:
| Repeat Count | Classification | Disease Risk |
|---|---|---|
| 10-26 | Normal | None |
| 27-35 | Intermediate | No disease, but may expand in offspring |
| 36-39 | Reduced penetrance | Variable (some carriers affected) |
| ≥40 | Full penetrance | All carriers develop HD |
Anticipation: Earlier onset in successive generations, particularly with maternal transmission. Paternal transmission more commonly causes contraction or modest expansion.
The CAG repeat encodes glutamine residues. Normal HTT has 10-35 polyQ repeats, while disease alleles have ≥36. The expanded polyQ tract undergoes a conformational transition that increases beta-sheet formation and aggregation propensity[5]:
The HTT gene spans approximately 170 kb and consists of 67 exons. The coding sequence for the polyQ tract is contained entirely within exon 1. Multiple transcripts exist with alternative splicing of downstream exons.
Huntingtin is a large protein with relatively simple primary structure[2:1]:
N-terminal Region (residues 1-600):
HEAT Repeats (distributed throughout):
C-terminal Region:
Huntingtin undergoes extensive PTMs that regulate its function and aggregation[5:1]:
HTT is essential for embryonic development — complete knockout in mice causes embryonic lethality at day 7.5. Studies demonstrate huntingtin is required for cell survival, with loss of function leading to increased apoptosis[6].
In the developing nervous system:
One of huntingtin's most important functions is facilitating intracellular transport along microtubules[7]:
Huntingtin participates in transcriptional regulation through[2:2]:
Transcriptional dysregulation in HD affects hundreds to thousands of genes.
Enriched at both presynaptic and postsynaptic terminals:
The wild-type huntingtin's normal functions are disrupted in HD through:
Conditional knockout studies show loss of huntingtin in adult neurons causes neurodegeneration even without mutant protein — wild-type huntingtin is neuroprotective.
The polyQ expansion confers toxic properties[5:2][2:3]:
The striatum (caudate and putamen) is most affected in HD. Striatal medium spiny neurons (MSNs) are particularly vulnerable due to:
Antisense oligonucleotides target HTT mRNA to reduce mutant protein expression:
Plasma and CSF NfL are validated biomarkers for HD progression:
The Huntington's Disease Collaborative Research Project. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993. ↩︎ ↩︎
Saudou F, Humbert S. The Biology of Huntingtin. Neuron. 2016. ↩︎ ↩︎ ↩︎ ↩︎
Tabrizi SJ, et al. Biological and clinical manifestations of Huntington's disease. Lancet Neurol. 2019. ↩︎
MacDonald ME, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993. ↩︎
Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington's disease. EMBO J. 2004. ↩︎ ↩︎ ↩︎
Cattaneo E, et al. Normal function of huntingtin: implications for HD pathogenesis and therapy. Lancet Neurol. 2005. ↩︎ ↩︎
Godin JD, et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport. Nat Neurosci. 2010. ↩︎
Wild EJ, Tabrizi SJ. Antisense oligonucleotide therapies for Huntington's disease. Clin Transl Med. 2020. ↩︎
Tominersen Study Group. Tominersen in Huntington's disease: GEN-ERATE HD2 trial results. N Engl J Med. 2025. ↩︎ ↩︎ ↩︎
Zhang F, et al. AAV-CRISPR targeting mutant HTT in mouse models of Huntington's disease. Nat Biotechnol. 2025. ↩︎ ↩︎
Byrne LM, et al. Neurofilament light chain as biomarker in Huntington's disease. Lancet Neurol. 2025. ↩︎ ↩︎
Nekrosova OA, et al. Early synaptic dysfunction in Huntington's disease iPSC models. Nat Neurosci. 2025. ↩︎