HTT — Huntingtin Gene Entity Page

HTT — Huntingtin Gene Entity Page

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HTT — Huntingtin</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>HTT</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Huntingtin</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>4p16.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3064" target="_blank">3064</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000197393" target="_blank">ENSG00000197393</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/143100" target="_blank">143100</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P42858" target="_blank">P42858</a></td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>3,144 amino acids (~350 kDa)</td>
</tr>
<tr>
<td class="label">Disease</td>
<td><a href="/diseases/huntingtons-disease">Huntington's Disease</a></td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Striatum (caudate/putamen), Cortex, Hippocampus, Cerebellum</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Polyglutamine Repeat</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Normal: 10-35 repeats | Disease: ≥36 repeats | Juvenile: >60 repeats</td>
</tr>
</table>

HTT — Huntingtin Gene Entity

Overview

HTT — Huntingtin Gene Entity Page

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HTT — Huntingtin</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>HTT</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Huntingtin</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>4p16.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3064" target="_blank">3064</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000197393" target="_blank">ENSG00000197393</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/143100" target="_blank">143100</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P42858" target="_blank">P42858</a></td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>3,144 amino acids (~350 kDa)</td>
</tr>
<tr>
<td class="label">Disease</td>
<td><a href="/diseases/huntingtons-disease">Huntington's Disease</a></td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Striatum (caudate/putamen), Cortex, Hippocampus, Cerebellum</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Polyglutamine Repeat</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Normal: 10-35 repeats | Disease: ≥36 repeats | Juvenile: >60 repeats</td>
</tr>
</table>

HTT — Huntingtin Gene Entity

Overview

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](/diseases/huntingtons) pathogenesis. The gene was identified in 1993 when the CAG trinucleotide repeat expansion responsible for HD was discovered[@huntingtons1993]. Huntingtin is one of the largest proteins in the human proteome at 3,144 amino acids (~350 kDa) and performs essential functions in [neurons](/entities/neurons) including intracellular transport, gene transcription regulation, synaptic function, and cell survival[@saudou2016].

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[@tabrizi2019].

Gene Structure and Mutation

Genetic Basis of Huntington's Disease

Huntington's disease is caused by an autosomal dominant CAG trinucleotide repeat expansion in the first exon of HTT[@huntingtons1993][@macdonald1993]:

| 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.

Polyglutamine Expansion Mechanism

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[@landles2004]:

Genomic Organization

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.

Protein Structure

Domain Architecture

Huntingtin is a large protein with relatively simple primary structure[@saudou2016]:

N-terminal Region (residues 1-600):

• Polyglutamine tract (residues ~18-36 in normal protein)
• Polyproline tract (adjacent to polyQ)
• HEAT repeat domain (adaptor protein interactions)

• Huntingtin, Elongation factor 3, Protein phosphatase 2A, TOR1
• Form elongated superhelical structure
• Mediate interactions with >100 protein partners

• Multiple protein interaction domains
• Postsynaptic density enrichment

Post-Translational Modifications

Huntingtin undergoes extensive PTMs that regulate its function and aggregation[@landles2004]:

• Phosphorylation: S421 phosphorylation is neuroprotective; S434, T1003 also regulated
• Acetylation: At specific lysines, promotes autophagy-mediated clearance
• Sumoylation: Modulates aggregation and protein interactions
• Ubiquitination: Targets mutant huntingtin for degradation

Normal Biological Functions

Embryonic Development and Neuronal Survival

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[@cattaneo2005].

In the developing nervous system:

• Regulates neural progenitor cell proliferation and differentiation
• Supports neuronal migration during corticogenesis
• Conditional knockout in adult brain causes progressive neurodegeneration

Intracellular Transport

One of huntingtin's most important functions is facilitating intracellular transport along microtubules[@godin2010]:

• Acts as a scaffold organizing dynein and kinesin motors with their cargoes
• Critical for vesicle, organelle, and protein transport between cell body and synapses
• HAP40 (HTTIP4) mediates huntingtin association with endosomes
• PolyQ expansion impairs this transport function

Gene Transcription Regulation

Huntingtin participates in transcriptional regulation through[@saudou2016]:

• REST/NRSF sequestration: Keeps this neuronal gene repressor in cytoplasm
• p53 interactions: Alters cell survival pathways
• CBP coactivator recruitment: Activity-dependent gene expression
• Transcription factor interactions: Multiple nuclear partners affected

Synaptic Function

Enriched at both presynaptic and postsynaptic terminals:

• Regulates synaptic vesicle release through exocytosis proteins
• Modulates NMDA and AMPA receptor function
• Alters calcium signaling and excitotoxicity pathways
• Regulates inhibitory GABAergic signaling

Disease Pathogenesis

Loss of Normal Function

The wild-type huntingtin's normal functions are disrupted in HD through:

• Dominant-negative effect of mutant protein
• Transcriptional dysregulation
• Altered subcellular localization
• Sequestration of wild-type protein in aggregates[@cattaneo2005]

Gain of Toxic Function

The polyQ expansion confers toxic properties[@landles2004][@saudou2016]:

Striatal Vulnerability

The striatum (caudate and putamen) is most affected in HD. Striatal medium spiny neurons (MSNs) are particularly vulnerable due to:

• High metabolic demands
• Complex transcriptional programs regulated by huntingtin
• Integration of corticostriatal and thalamostriatal inputs
• Excitatory glutamatergic input from cortex

Therapeutic Approaches

ASO Therapy[@wild2020][@tominersen2025]

Antisense oligonucleotides target HTT mRNA to reduce mutant protein expression:

• Tominersen (RG6042/IONIS-HTTRx): Phase 3 trials showed dose-dependent mutant huntingtin lowering in CSF. The GENERATION HD1 trial was discontinued in 2021 due to unfavorable risk/benefit, but continued development with refined dosing protocols (GENERATION HD2)[@tominersen2025]
• Other ASOs: Multiple candidates in development targeting different HTT regions
• Allele-selective approaches: For specific mutations

Gene Editing[@aavcrispr2025]

• CRISPR/Cas9 approaches to selectively silence mutant HTT
• AAV delivery of gene editing machinery
• Base editing and prime editing strategies

Small Molecule Approaches

• Hsp90 inhibitors: Promote mutant huntingtin degradation
• HDAC inhibitors: Modulate transcription
• PDE10 inhibitors: Modulate striatal signaling

Neuroprotective Strategies

• BDNF-enhancing therapies
• Mitochondrial stabilizers
• Anti-inflammatory approaches

Biomarkers

Neurofilament Light Chain (NfL)[@neurofilament2025]

Plasma and CSF NfL are validated biomarkers for HD progression:

• Elevated in HD mutation carriers vs controls
• Correlates with disease stage and progression rate
• Used in clinical trials to monitor treatment effects

Imaging

• MRI: Volumetric changes in striatum, cortex
• PET: Monoamine oxidase B ligands, synaptic vesicle proteins
• fMRI: Functional connectivity changes

Clinical Endpoints

• TMS: Motor and cognitive measures
• Cognitive assessments: SDMT, symbol digit modalities
• Behavioral measures: Problem behaviors scale

Mechanistic Pathway: HTT in Huntington's Disease

Recent Research (2025-2026)

• 2025: Tominersen (ASO therapy) GEN-ERATE HD2 trial results in N Engl J Med — refined dosing protocols[@tominersen2025]
• 2025: AAV-CRISPR delivery targeting mutant HTT in mouse models shows promise for gene editing approaches[@aavcrispr2025]
• 2025: Neurofilament light chain validated as robust biomarker for HD progression and trial endpoints[@neurofilament2025]
• 2025: Early synaptic dysfunction identified in HD patient-derived iPSC models[@early2025]
• Understanding disease-modifying mechanisms continues to advance

See Also

• [HTT Gene Page](/genes/htt) — Comprehensive gene-level page
• [Huntington's Disease](/diseases/huntingtons)
• [Polyglutamine Expansion Pathway](/mechanisms/polyglutamine-aggregation)
• [Striatal Medium Spiny Neurons](/cell-types/striatal-medium-spiny-neurons)
• [Transcription Dysregulation in HD](/mechanisms/transcriptional-dysregulation-huntingtons)
• [Huntington's Disease Treatment](/therapeutics/huntington-disease-treatment)

External Links

• NCBI Gene: [3064](https://www.ncbi.nlm.nih.gov/gene/3064)
• Ensembl: [ENSG00000197393](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000197393)
• OMIM: [143100](https://omim.org/entry/143100)
• UniProt: [P42858](https://www.uniprot.org/uniprot/P42858)
• CHDI Foundation: [Huntington's Disease Therapeutics](https://www.chdifoundation.org/)
• Allen Human Brain Atlas: [HTT expression](https://human.brain-map.org/microarray/search/show?search_term=HTT)