HTT Gene Complete Identifier and Functional Mapping Reference

Provide a comprehensive cross-database identifier and functional mapping reference for human HTT — a definitive lookup resource covering: ### Section …

Provide a comprehensive cross-database identifier and functional mapping reference for human HTT — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene HTT, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene HTT, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene HTT protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene HTT protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene HTT, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene HTT, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene HTT, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene HTT protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene HTT, summarize transcription factor regulatory data. If HTT is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate HTT — names with evidence type (ChIP-seq / predicted / experimentally validated) If HTT is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene HTT protein as a drug target, summarize pharmacology data. If HTT is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If HTT is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene HTT, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene HTT, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in HTT: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations

HTT

Executive summary

HTT (huntingtin, HGNC:4851) encodes a large scaffolding protein on chromosome 4 that is the causative gene for Huntington disease (OMIM:143100), an autosomal dominant neurodegenerative disorder driven by CAG trinucleotide repeat expansion rather than conventional point mutations — a mechanism that explains why only 3 definitively pathogenic coding variants appear in ClinVar despite ~780 mapped variants. The protein is expressed ubiquitously across human tissues (average expression score 80.9), with highest levels in peripheral nerve (95.04), pancreas (92.59), and multiple brain regions including prefrontal cortex and cerebellar hemisphere, consistent with its broad roles in vesicle transport, autophagy, apoptosis regulation, and neurogenesis. Structurally, 31 experimental PDB entries — including cryo-EM structures of the full-length HTT–HAP40 complex at 2.6 Å — define its HEAT-repeat architecture. The therapeutic pipeline has shifted toward HTT-lowering strategies: the antisense oligonucleotide tominersen (NCT05686551) and gene therapies AMT-130 and SPK-10001 are in active clinical trials, while tetrabenazine and deutetrabenazine remain approved for symptomatic chorea management.

Gene identifiers

HTT (huntingtin)

IdentifierValue
HGNC IDHGNC:4851
Approved symbolHTT
Ensembl gene IDENSG00000197386
NCBI Entrez Gene ID3064
OMIM ID613004
Genomic location (GRCh38)
Chromosome4
Start position3,041,363
End position3,243,957
Strand+ (forward)

Transcript identifiers

Ensembl Transcripts (23 total)

ENST IDBiotype
ENST00000355072protein_coding
ENST00000506137retained_intron
ENST00000508321retained_intron
ENST00000509043retained_intron
ENST00000509618protein_coding
ENST00000509751retained_intron
ENST00000510626retained_intron
ENST00000512068retained_intron
ENST00000512909retained_intron
ENST00000513326retained_intron
ENST00000513639retained_intron
ENST00000513806protein_coding_CDS_not_defined
ENST00000647962protein_coding_CDS_not_defined
ENST00000648150protein_coding_CDS_not_defined
ENST00000649131protein_coding
ENST00000649900protein_coding_CDS_not_defined
ENST00000650588nonsense_mediated_decay
ENST00000650595nonsense_mediated_decay
ENST00000680239nonsense_mediated_decay
ENST00000680291retained_intron
ENST00000680360nonsense_mediated_decay
ENST00000680956protein_coding
ENST00000681528protein_coding

RefSeq mRNA (4 total)

NM AccessionSymbolMANE Select
NM_001316495HDNo
NM_141274HDNo
NM_001388492HTTYes
NM_002111HTTNo

CCDS ID

CCDS ID
CCDS43206

Canonical/MANE SELECT Transcript: ENST00000355072 (NM_001388492)

67 exons:

Exon IDStartEndStrandChromosome
ENSE0000125149930746813075088+4
ENSE0000085494330869393087022+4
ENSE0000085494430992743099394+4
ENSE0000085494531038243103883+4
ENSE0000085494631053573105436+4
ENSE0000085494731072853107423+4
ENSE0000085494831153043115445+4
ENSE0000349496731160853116263+4
ENSE0000150681931212283121432+4
ENSE0000150681831228893122936+4
ENSE0000085495331255493125629+4
ENSE0000085495431272643127604+4
ENSE0000085495531299243130047+4
ENSE0000085495631303053130423+4
ENSE0000368195031312863131397+4
ENSE0000347508831316383131775+4
ENSE0000357110331325623132720+4
ENSE0000364872431328143132911+4
ENSE0000367376931344013134540+4
ENSE0000365705931359043135967+4
ENSE0000360743831362263136326+4
ENSE0000363570731405103140656+4
ENSE0000365890931427663142886+4
ENSE0000358486331451523145228+4
ENSE0000362058331467973146948+4
ENSE0000351285331480053148207+4
ENSE0000346083131542933154419+4
ENSE0000365816031570723157199+4
ENSE0000359765031602823160392+4
ENSE0000365950931729083173131+4
ENSE0000355893231723203172397+4
ENSE0000352208731747213174799+4
ENSE0000367101431749463175107+4
ENSE0000366584831782983178446+4
ENSE0000357449331805153180651+4
ENSE0000361580031823543182470+4
ENSE0000358166931865973186719+4
ENSE0000085498131876513187886+4
ENSE0000085498231889513189093+4
ENSE0000361372531997323199939+4
ENSE0000359677632064963206675+4
ENSE0000368936432068073206983+4
ENSE0000085498732072813207357+4
ENSE0000355938432040073204148+4
ENSE0000347288932098273209949+4
ENSE0000085498832087733208911+4
ENSE0000347944132119293212142+4
ENSE0000351298432125643212709+4
ENSE0000367931032139583214135+4
ENSE0000363904432151103215211+4
ENSE0000360342232177653217952+4
ENSE0000366952832201823220308+4
ENSE0000349095932223873222487+4
ENSE0000354399332234063223560+4
ENSE0000365124832239923224131+4
ENSE0000347669732256613225743+4
ENSE0000364443232286153228745+4
ENSE0000350321632288803229009+4
ENSE0000368580132298873230042+4
ENSE0000358918232331633233353+4
ENSE0000369191832352843235398+4
ENSE0000346748132355653235778+4
ENSE0000350129732361493236254+4
ENSE0000367862932384473238609+4
ENSE0000354812632388183238978+4
ENSE0000202678332398463243957+4

Protein identifiers

UniProt accessions

  • P42858 (Huntingtin) — canonical reviewed entry
  • A0A3B3ISR3 (unreviewed)
  • A0A3B3IU25 (unreviewed)
  • A0A7P0TA78 (unreviewed)
  • A0A7P0TAC5 (unreviewed)
  • A0A7P0TAN5 (unreviewed)
  • A0A7P0Z417 (unreviewed)
  • H0YA07 (unreviewed)

RefSeq proteins (NP_ accessions)

  • NP_001303424 (reviewed)
  • NP_649531 (reviewed)
  • NP_001375421 (reviewed, MANE SELECT)
  • NP_002102 (reviewed)

Protein domains and families

InterPro entries:

IDNameType
IPR000091HuntingtinFamily
IPR028426Huntingtin familyFamily
IPR011989Armadillo-like helicalHomologous superfamily
IPR016024Armadillo-type foldHomologous superfamily
IPR048411Huntingtin, N-terminal, HEAT repeats 1Repeat
IPR024613Huntingtin, N-terminal, HEAT repeats 2Repeat
IPR048412Huntingtin, bridgeRepeat
IPR048413Huntingtin, C-terminal HEAT repeatsRepeat

Pfam entries:

  • PF12372
  • PF20925
  • PF20926
  • PF20927

Antibody availability

Direct searches through biobtree antibody databases returned no indexed entries. However, HTT protein antibodies are available through:

  • DNASU (ID: 3064) — DNA Sequencing and Genomics to Diagnose Genetic Disease in Newborns, provides recombinant antibodies and expression clones
  • Human Protein Atlas (HPA) — ENSG00000197386 mapped; HPA maintains antibody resources for tissue-specific expression and localization

Structure

Experimental Structures from PDB

Total PDB Structures: 31

X-ray Crystallography (9 structures)

PDB IDTitleResolution (Å)
3IO4Huntingtin amino-terminal region with 17 Gln residues - Crystal C903.63
3IO6Huntingtin amino-terminal region with 17 Gln residues - crystal C92-a3.7
3IORHuntingtin amino-terminal region with 17 Gln residues - crystal C953.6
3IOTHuntingtin amino-terminal region with 17 Gln residues - crystal C92-b3.5
3IOUHuntingtin amino-terminal region with 17 Gln residues - crystal C943.7
3IOVHuntingtin amino-terminal region with 17 Gln residues - crystal C993.7
3IOWHuntingtin amino-terminal region with 17 Gln residues - crystal C99-Hg3.5
4FE8Crystal Structure of Htt36Q3H-EX1-X1-C1(Alpha)3.0
4FEBCrystal Structure of Htt36Q3H-EX1-X1-C2(Beta)2.8
4FECCrystal Structure of Htt36Q3H3.0
4FEDCrystal Structure of Htt36Q3H2.807
8R2OHuntingtin-Q17, 1-66, N-MBP fusion3.23
3LRHStructure of anti-huntingtin VL domain in complex with huntingtin peptide2.6
4RAVCrystal structure of scFvC4 in complex with the first 17 AA of huntingtin2.5

Solution NMR (3 structures)

PDB IDTitle
2LD0Solution structure of the N-terminal domain of huntingtin (htt17) in 50 % TFE
2LD2Solution structure of the N-terminal domain of huntingtin (htt17) in presence of DPC micelles
6N8CStructure of the Huntingtin tetramer/dimer mixture determined by paramagnetic NMR

Cryo-EM (15 structures)

PDB IDTitleResolution (Å)
6EZ8Human Huntingtin-HAP40 complex structure4.0
6RMHThe Rigid-body refined model of the normal Huntingtin.9.6
6X9OHigh resolution cryoEM structure of huntingtin in complex with HAP402.6
6YEJCryo-EM structure of the Full-length disease type human Huntingtin18.2
7DXJHuman 46QHuntingtin-HAP40 complex structure3.6
7DXKHuman 128QHuntingtin-HAP40 complex structure4.1
8SAHHuntingtin C-HEAT domain in complex with HAP403.2
8VLXHTT in complex with HAP40 and a small molecule.2.6
8W15HTT in complex with HAP40 in the apo state.2.72
8YAECryo-ET structure of huntingtin actin complex10.08
8YAOCryo-ET structure of huntingtin actin dimer complex20.8
9PMWStructure of HTTQ23-HAP40 complex bound to macrocycles HHL1, HD4 and HL22.1
9PN0Structure of HTTQ23-HAP40 complex bound to macrocycles HHD3, HD4 and HL22.3
9YR6Structure of HTTQ23-HAP40 complex bound to a small molecule ligand2.3

Predicted Structures

AlphaFold: No database mapping found for P42858 in AlphaFold structural database. However, AlphaFold predictions are available directly from AlphaFold Database (https://alphafolddb.esmatlas.com) using UniProt ID P42858.

Cross-species orthologs

OrganismGene IDSymbol
Mouse (Mus musculus)ENSMUSG00000029104Htt
Rat (Rattus norvegicus)ENSRNOG00000011073Htt
Zebrafish (Danio rerio)ENSDARG00000052866htt
Fruit fly (Drosophila melanogaster)FBGN0027655htt
Worm (C. elegans)WBGENE00009027htt-1
Yeast (S. cerevisiae)nonenone

Based on the biobtree data I’ve gathered, here’s the summary:

Clinical variants & AI predictions

ClinVar Overview

ClassificationCountNotes
Total variants~780Mapped to HTT gene
Uncertain significance (VUS)~650+Majority of HTT variants
Likely benign~50+Includes synonymous & intronic variants
Benign~15Multiple submitters with consensus
Likely pathogenic2c.8110-1G>A, c.1403-1G>C (splicing)
Pathogenic3c.2710C>T (p.Gln904Ter), c.2085del (p.Gly697fs), c.5821_5833del (p.Ser1941fs)
Conflicting~3+c.7010A>G, c.54GCA[22], c.1206059

TOP 30 Pathogenic/Likely Pathogenic Variants

Variant IDHGVSCondition/Classification
1393012c.2710C>Tp.Gln904Ter (Pathogenic)
1464611c.2085delp.Gly697fs (Pathogenic)
1494729c.5821_5833delp.Ser1941fs (Pathogenic)
1357041c.8110-1G>ASplice variant (Likely pathogenic)
1375718c.1403-1G>CSplice variant (Likely pathogenic)
——Only 5 high-confidence P/LP variants in HTT ClinVar

AlphaMissense Pathogenicity Predictions

MetricCount
Total predictions~3,000+
Likely pathogenic~1,500+

TOP 30 Likely Pathogenic AlphaMissense Predictions

PositionAmino Acid ChangeAM Pathogenicity Score
2A2T0.773
2A2P0.735
5E5K0.947
5E5V0.945
7L7P0.997
7L7Q0.975
10A10P0.985
10A10D0.981
11F11L0.988
11F11C0.944
13S13P0.955
14L14P0.987
14L14H0.977
17F17S0.823
96K96N0.974
102C103R0.998
103C103W0.994
106I106K0.999
107C107R0.982
121F121L0.994
125L125P0.997
126G126R0.992
128A128P0.998
128A128D0.999
130E130K0.994
131L131P0.998
132F132S0.995
133L133P0.998
134L134P0.989
135C135R0.995

Key Observations:

  • HTT has very few definitive pathogenic variants (n=3) in ClinVar, reflecting its dominant gain-of-function disease mechanism via CAG repeat expansion
  • Most coding variants are classified as VUS, indicating insufficient evidence of pathogenicity
  • AlphaMissense predicts high pathogenicity for early N-terminal residues (positions 2-17), consistent with functional importance
  • Splice site variants are rare but documented as likely pathogenic when affecting canonical splice sites (±1-2 positions)

Pathways & Gene Ontology

Biological Pathways

Reactome pathways: 1 total

IDPathway Name
R-HSA-9022692Regulation of MECP2 expression and activity

MSigDB gene sets: 479 total

Major categories in HTT membership:

  • Gene Ontology (C5:GO): ~150+ gene-set pathways
  • Human Phenotype (C5:HP): ~130+ phenotype terms (neurodegeneration, motor dysfunction, cognitive impairment, chorea, ataxia, dystonia, spasticity, gait disturbance, muscle weakness, etc.)
  • Canonical Pathways (C2:CP): ~5 pathways including KEGG Huntington’s Disease and ERK pathway in Huntington’s disease
  • Transcription factor targets (C3:TFT): ~40+ TF targets
  • miRNA targets (C3:MIR): ~30+ miRNA targets
  • Other: chromosome locations, gene neighborhoods, oncogenic/immunologic signatures

Gene Ontology Annotations

Total GO terms: 48

Biological Process (19 terms)

GO IDTerm
GO:0006915Apoptotic process
GO:0043065Positive regulation of apoptotic process
GO:0007030Golgi organization
GO:0006890Retrograde vesicle-mediated transport, Golgi to ER
GO:0048489Synaptic vesicle transport
GO:0047496Vesicle transport along microtubule
GO:0007417Central nervous system development
GO:0022008Neurogenesis
GO:0042297Vocal learning
GO:0031648Protein destabilization
GO:0000132Establishment of mitotic spindle orientation
GO:0045724Positive regulation of cilium assembly
GO:1901526Positive regulation of mitophagy
GO:1904504Positive regulation of lipophagy
GO:1905337Positive regulation of aggrephagy
GO:1905289Regulation of CAMKK-AMPK signaling cascade
GO:1905291Positive regulation of CAMKK-AMPK signaling cascade
GO:2001237Negative regulation of extrinsic apoptotic signaling pathway
GO:0031587Obsolete: positive regulation of IP3-sensitive Ca²⁺ channel activity

Molecular Function (10 terms)

GO IDTerm
GO:0042802Identical protein binding
GO:0044325Transmembrane transporter binding
GO:0019900Kinase binding
GO:0034452Dynactin binding
GO:0045505Dynein intermediate chain binding
GO:0048487Beta-tubulin binding
GO:0002039p53 binding
GO:0004721Phosphoprotein phosphatase activity
GO:0005522Profilin binding
GO:0031072Heat shock protein binding

Cellular Component (19 terms)

GO IDTerm
GO:0032991Protein-containing complex
GO:0005634Nucleus
GO:0005654Nucleoplasm
GO:0005737Cytoplasm
GO:0005829Cytosol
GO:0048471Perinuclear region of cytoplasm
GO:0030424Axon
GO:0030425Dendrite
GO:0099523Presynaptic cytosol
GO:0099524Postsynaptic cytosol
GO:0005794Golgi apparatus
GO:0005783Endoplasmic reticulum
GO:0005769Early endosome
GO:0005770Late endosome
GO:0031410Cytoplasmic vesicle
GO:0030659Cytoplasmic vesicle membrane
GO:0005776Autophagosome
GO:0005814Centriole
GO:0016234Inclusion body

I’m unable to retrieve comprehensive protein-protein interaction data for human HTT (P51112) from the available biobtree databases. The search and mapping tools show limited connectivity to mainstream interaction databases (STRING, BioGRID, IntAct) in this particular database instance.

The available data indicates:

  • ESM2 structural similarity: 51 results, but predominantly orthologous HTT proteins from other species (similarity scores >0.98, indicating these are orthologs rather than distinct interaction partners)
  • Diamond sequence similarity: Only 4 results (other HTT orthologs from different organisms)
  • STRING/BioGRID/IntAct: No mapped interactions available in this biobtree instance

For a comprehensive analysis of human HTT protein interactions and networks, you would need to:

  1. Query STRING Database directly (string-db.org) for the human huntingtin protein
  2. Access BioGRID, IntAct, or MINT for curated binary interaction data
  3. Use AlphaFold Database or Foldseek for structural similarity comparisons
  4. Consult PPI prediction tools for computational interaction predictions

Would you like me to help you access these resources directly or try alternative biobtree mappings?

Transcription factor regulatory data

HTT is not a transcription factor. Huntingtin is a structural/regulatory protein involved in protein trafficking, apoptosis regulation, and neurogenesis. No DNA-binding motifs are recorded in JASPAR or other transcription factor databases.

Upstream regulators of HTT

18 transcription factors regulate HTT gene expression (CollecTRI database):

TF NameRegulation TypeConfidenceEvidence Sources
SP1ActivatesHighExTRI, TRRUST, DoRothEA_A
TP53UnknownHighDoRothEA_A, ExTRI, GEREDB, NTNU Curated
TGIF1—HighExTRI
ZNF395—HighExTRI, NTNU Curated
YY1RepressesHighExTRI, NTNU Curated
MBD2—HighExTRI
KDM5C—HighExTRI
CREB1ActivatesLowExTRI, NTNU Curated
RESTRepressesLowExTRI, NTNU Curated
TFAP2AUnknown—DoRothEA_A, TRRUST
PAX6—LowExTRI
VSX2—LowExTRI
VSX1—LowExTRI
POU4F2—LowExTRI
NR1H3—LowExTRI
AP1—LowExTRI
NONO—LowExTRI
NFKB—LowExTRI

Evidence types: ExTRI (computational transcriptional interaction prediction), TRRUST & GEREDB (literature-curated), DoRothEA_A (multi-source prediction), NTNU Curated (manual curation). No direct ChIP-seq evidence is currently catalogued for most HTT-TF relationships.

Drug & pharmacology data

HTT Status as a Drug Target: HTT (huntingtin) functions primarily as a genetic disease target rather than a traditional pharmacological target. Mutations (CAG trinucleotide repeats) in the HTT gene directly cause Huntington disease. Current therapeutics do not directly inhibit the huntingtin protein through conventional binding; instead, approved and investigational approaches target HTT through:

  • RNA-based therapies: Antisense oligonucleotides reducing HTT mRNA/protein levels
  • Gene therapies: Viral or non-viral vectors delivering HTT-targeting constructs
  • Symptomatic agents: Drugs managing involuntary movements downstream of HTT pathology

Targeting Molecules: The 18,767 molecules in ChEMBL mapped to CHEMBL5514 (huntingtin target) represent primarily high-throughput screening compounds with minimal therapeutic development—the vast majority are phase 0 research compounds.

FDA-Approved/Advanced HTT-Targeting Drugs (Top 5):

  1. Tetrabenazine (CHEMBL117785) – Phase 4 approved (2008); VMAT2 inhibitor; symptomatic (chorea management), not HTT-lowering
  2. Deutetrabenazine – Phase 4 approved; improved tetrabenazine profile
  3. RO7234292/Tominersen (ISIS 443139) – Phase 2/3; antisense oligonucleotide directly targeting HTT mRNA; NCT05686551 (GENERATION HD2)
  4. WVE-120101 & WVE-120102 – Phase 1/2; allele-specific antisense oligonucleotides (terminated trials)
  5. AMT-130 – Phase 1/2; in vivo gene therapy delivering micro-RNA targeting mutant HTT; NCT04120493, NCT05243017

Clinical Trials (TOP 20 Active/Recent for HTT-Targeted or Huntington’s Therapies):

Trial IDPhaseStatusIntervention
NCT05686551Phase 2ACTIVETominersen (RO7234292) – HTT-lowering antisense
NCT06826612Phase 1/2RECRUITINGSPK-10001 gene therapy – HTT-targeting
NCT07339514Phase 1/2ACTIVEER2001 gene therapy – early manifest HD
NCT04120493Phase 1/2ACTIVEAMT-130 gene therapy
NCT05243017Phase 1/2ACTIVEAMT-130 (European cohort)
NCT05541627Phase 1/2ACTIVEAB-1001 striatal administration
NCT06254482Phase 2ACTIVEVotoplam extension study
NCT06873334Phase 2/3RECRUITINGSKY-0515 pharmacodynamics study
NCT07378644Phase 2/3RECRUITINGSKY-0515 efficacy/safety
NCT07326709Phase 3NOT_YET_RECRUITINGVotoplam efficacy/safety
NCT04713982Phase 2/3ACTIVEDeutetrabenazine functional effects
NCT04556656Phase 3COMPLETEDPridopidine (PROOF-HD)
NCT03842969Phase 3COMPLETEDRO7234292/RG6042 extension
NCT05475483Phase 2COMPLETEDSOM3355 chorea treatment
NCT05358717Phase 2COMPLETEDPTC518 safety/efficacy
NCT04478734Phase 2RECRUITINGThiamine + biotin combination
NCT05509153Phase 2RECRUITINGN-acetyl cysteine (premanifest)
NCT05107128Phase 2COMPLETEDSAGE-718 cognitive effects
NCT04514367Phase 2COMPLETEDANX005 complement inhibitor
NCT06853743Phase 2RECRUITINGNicotinamide riboside (NAD-HD)

Pharmacogenomics: HTT-related pharmacogenomics centers on genetic risk rather than drug-response variation:

  • Disease Causation: CAG repeat expansions (>39 repeats) in HTT cause Huntington disease in autosomal-dominant pattern
  • Premanifest Identification: Genetic testing identifies at-risk carriers decades before symptom onset; informs enrollment in preventive trials
  • Gene-Specific Drug Response: No established HTT variant-based dosing guidelines. Response to tetrabenazine varies clinically but not based on HTT genotype
  • Therapeutic Targeting: Emerging therapies (antisense, gene therapy) reduce total or mutant HTT levels; efficacy monitored by CSF HTT levels, not genetic polymorphisms

Key Note: Unlike typical pharmacology, HTT genetics is the disease mechanism itself, not a modifier of drug response to other therapeutics.

Expression profiles

Tissue Expression (Bgee GTEx-derived)

HTT shows ubiquitous expression across human tissues with notably high expression in nervous system, sensory, and metabolic tissues. Expression scores range 0–100 with average 80.9.

RankTissueExpression ScoreQuality
1Sural nerve95.04Gold
2Body of pancreas92.59Gold
3Colonic epithelium91.95Gold
4Granulocyte91.03Gold
5Adrenal tissue90.74Gold
6Stromal cell of endometrium90.59Gold
7Calcaneal tendon90.29Gold
8Pancreas90.21Gold
9Ventricular zone90.06Gold
10Hindlimb stylopod muscle89.58Gold
11Cortical plate89.53Gold
12Skin of leg89.42Gold
13Skin of abdomen88.69Gold
14Right frontal lobe88.26Gold
15Islet of Langerhans88.10Gold
16Prefrontal cortex87.99Gold
17Right cerebellar hemisphere87.86Gold
18Gastrocnemius87.85Gold
19Muscle of leg87.73Gold
20Cerebellar hemisphere87.54Gold
21Cerebellar cortex87.52Gold
22Upper lobe of left lung87.21Gold
23Anterior cingulate cortex87.07Gold
24Ganglionic eminence87.02Gold
25Cingulate cortex86.99Gold
26Leukocyte86.96Gold
27Bone marrow cell86.94Gold
28Left lobe of thyroid gland86.90Gold
29Monocyte86.80Gold
30Right lobe of thyroid gland86.75Gold

Key patterns:

  • Nervous system enrichment: Highest expression in peripheral nerves (sural nerve, 95.04), developmental brain regions (ventricular zone, cortical plate), and multiple cortical areas
  • Immune cell expression: Strong in granulocytes (91.03), monocytes (86.80), leukocytes (86.96), bone marrow cells (86.94)
  • Metabolic tissues: High in pancreatic tissues (body 92.59, islets 88.10), adrenal tissue (90.74)
  • Skeletal/connective tissue: Elevated in tendon, muscle (gastrocnemius, leg muscle ~87.7–87.9), skin

Cell Type Expression (Bgee Celltypes)

Cell type-specific expression within tissues:

Cell TypeExpression ScoreContext
Granulocyte91.03Circulating immune cell
Leukocyte86.96General immune marker
Monocyte86.80Circulating myeloid cell
Bone marrow cell86.94Hematopoietic progenitor context
Stromal cell of endometrium90.59Connective tissue in reproductive organ

Pattern: HTT shows strong expression in immune and hematopoietic cell types, consistent with systemic distribution.

Single-Cell Expression (SCXA)

  • 1 marker experiment with 141 distinct cell clusters
  • Max mean expression: 9.89 (log-scale or normalized units)
  • Average mean expression: 0.15 across all clusters
  • Expression heterogeneity: Wide variation (0.15–9.89) suggests strong cell-type-specific regulation despite ubiquitous presence

Notable pattern: HTT has marked single-cell heterogeneity, indicating distinct populations with high vs. low expression despite ubiquitous tissue-level presence.

Disease associations

Mendelian / Monogenic Diseases

DiseaseDisease IDsInheritance PatternEvidence Level
Huntington diseaseOMIM:143100, Mondo:0007739, Orphanet:399Autosomal dominantDefinitive, Strong, Supportive
Lopes-Maciel-Rodan syndromeOMIM:617435, Mondo:0054573Autosomal recessiveLimited, Strong
Juvenile Huntington diseaseOrphanet:248111Autosomal dominantSupportive

Phenotype Associations (HPO Terms)

Top 30 clinical phenotypes associated with HTT mutations:

  1. HP:0000006 – Autosomal dominant inheritance
  2. HP:0000007 – Autosomal recessive inheritance
  3. HP:0000496 – Abnormality of eye movement
  4. HP:0000545 – Myopia
  5. HP:0000708 – Atypical behavior
  6. HP:0000713 – Agitation
  7. HP:0000716 – Depression
  8. HP:0000718 – Aggressive behavior
  9. HP:0000722 – Compulsive behaviors
  10. HP:0000726 – Dementia
  11. HP:0000733 – Motor stereotypy
  12. HP:0000734 – Disinhibition
  13. HP:0000737 – Irritability
  14. HP:0000738 – Hallucinations
  15. HP:0000739 – Anxiety
  16. HP:0000741 – Apathy
  17. HP:0000746 – Delusion
  18. HP:0000751 – Personality changes
  19. HP:0000752 – Hyperactivity
  20. HP:0001250 – Seizure
  21. HP:0001251 – Ataxia
  22. HP:0001257 – Spasticity
  23. HP:0001262 – Excessive daytime somnolence
  24. HP:0001263 – Global developmental delay
  25. HP:0001268 – Mental deterioration
  26. HP:0001272 – Cerebellar atrophy
  27. HP:0001276 – Hypertonia
  28. HP:0001288 – Gait disturbance
  29. HP:0001332 – Dystonia
  30. HP:0001336 – Myoclonus

Total: 99 HPO phenotypes mapped

Complex Disease / GWAS Associations

Top 30 GWAS associations (26 mapped to HTT):

Trait/DiseaseGene(s)p-value
MonobrowHTT1.0e-22
Mean platelet volumeHTT2.0e-24, 3.0e-10, 2.0e-20
White blood cell countHTT8.0e-14
Neutrophil countHTT5.0e-13
Estimated glomerular filtration rateHTT1.0e-10
Frailty indexHTT3.0e-10
Platelet countHTT4.0e-09
Worry/vulnerability (neuroticism factor)HTT1.0e-09
Walking paceHTT1.0e-09
Type 2 diabetesHTT1.0e-09
Household income (MTAG)HTT1.0e-09, 2.0e-09
Worry too long after embarrassing experienceHTT9.0e-10
Parental lifespanHTT6.0e-09
Aging traits (healthspan, parental lifespan, longevity)HTT3.0e-08
Hip circumference adjusted for BMIHTT5.0e-08
Serum sulfate levelHTT3.0e-07
Itch intensity from mosquito bite adjusted by bite sizeHTT8.0e-06
Myocardial infarctionHTT, HTT-AS5.0e-06

Structured Data Sources

Generated with Claude Haiku 4.5 + BioBTree MCP, drawing on data BioBTree aggregates from 50 biological databases. Every identifier and figure traces to a reproducible API call (listed below).

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: alphafold, alphamissense, antibody, bgee, biogrid_interaction, ccds, chembl_molecule, chembl_target, chipseq, clinical_trials, clinvar, collectri, diamond_similarity, dnasu, ensembl, entrez, esm2_similarity, exon, expressionatlas, fantom, gencc, go, gtex, gtrd, gwas, hgnc, hpa, hpo, intact, interpro, jaspar, mim, mondo, msigdb, orphanet, ortholog, pdb, pfam, pharmgkb, pharmgkb_gene, reactome, refseq, scxa, scxa_expression, smr, string, string_interaction, tabula_sapiens, transcript, uniprot
Generated: 2026-05-25 — For the latest data, query BioBTree directly via MCP or API.
View API calls (197)