HTT Gene (Huntingtin): Structure, Function, and Clinical Significance
A comprehensive biomedical overview of the HTT gene, its protein product, associated diseases, expression patterns, and mutation landscape.
Gene Information Card
| Symbol | HTT |
|---|---|
| Full Name | Huntingtin |
| Gene Type | Protein coding |
| Chromosomal Location | 4p16.3 |
| NCBI Gene ID | 3064 ncbi.nlm.nih.gov/gene/3064 |
| Ensembl ID | ENSG00000197386 |
| UniProt ID | P42858 |
| OMIM ID | 613004 |
| HGNC ID | 4851 |
| Aliases | HD; IT15; C6orf2A; LOMARS |
Description
The HTT gene encodes huntingtin, a large (348 kDa) protein with no clear homology to other proteins. It is ubiquitously expressed but shows highest levels in the brain. Huntingtin is involved in multiple cellular processes including vesicular trafficking, endocytosis, autophagy, and transcriptional regulation. The gene contains a polymorphic CAG trinucleotide repeat in its first exon; expansion beyond 35 repeats causes Huntington disease (HD), a progressive neurodegenerative disorder. The repeat length inversely correlates with age of onset. HTT is essential for embryonic development, and its loss-of-function is lethal in mice. The protein undergoes proteolytic cleavage, and mutant huntingtin fragments aggregate and cause neurotoxicity.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Huntington disease (HD) | Expansion of CAG repeat (>35) in exon 1 leads to production of mutant huntingtin with expanded polyglutamine tract. This confers a toxic gain-of-function, causing neuronal dysfunction and death, particularly in striatal medium spiny neurons. Loss of normal huntingtin function may also contribute. | OMIM #143100; ClinVar; NCBI Gene |
| Huntington disease-like 2 (HDL2) | Not directly caused by HTT mutations; but HTT CAG repeat expansion is the primary cause of HD. HDL2 is caused by CTG expansion in JPH3, but differential diagnosis includes HTT testing. | OMIM #606438; ClinVar |
| Other polyglutamine disorders | HTT is the archetype for polyglutamine diseases; other genes with CAG repeats cause similar disorders, but HTT mutations are specific to HD. | OMIM; NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | High | Highest expression in neurons; critical for neuronal function. |
| Testis | Moderate | Expressed in spermatids; role in spermatogenesis. |
| Heart | Moderate | Expressed in cardiac muscle; function not fully characterized. |
| Liver | Low | Low expression; role in hepatic metabolism unclear. |
| Kidney | Low | Low expression; function not well defined. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | High | Neuronal-like cells; used for HD modeling. |
| HeLa (cervical carcinoma) | Moderate | Ubiquitous expression; used for basic studies. |
| HEK293 (embryonic kidney) | Moderate | Common cell line for overexpression studies. |
| U87 (glioblastoma) | Low | Glial cells; lower expression compared to neurons. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| CAG repeat expansion (36-39) | Pathogenic (reduced penetrance) | Variable; may or may not cause HD | Expanded polyglutamine tract; increased risk of HD with incomplete penetrance. |
| CAG repeat expansion (≥40) | Pathogenic (full penetrance) | ~1-2 per 100,000 worldwide | Causes HD; length inversely correlates with age of onset. |
| CAG repeat expansion (≥60) | Pathogenic (juvenile onset) | Rare | Very early onset HD; often paternal transmission. |
| Normal CAG repeat (≤35) | Benign | Most common | No disease association. |
Mutation functional classification
Loss of Function (LOF)
Loss of normal huntingtin function may contribute to HD pathogenesis, as huntingtin is essential for embryonic development and cellular homeostasis. However, HD is primarily considered a gain-of-function disease.
Gain of Function (GOF)
Expanded polyglutamine tract confers a toxic gain-of-function. Mutant huntingtin misfolds, aggregates, and interacts aberrantly with proteins, leading to neuronal dysfunction and death.
Dominant Negative (DN)
Mutant huntingtin may exert a dominant-negative effect by interfering with normal huntingtin's functions, such as vesicular trafficking and autophagy, through protein-protein interactions.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Huntington disease pathway (KEGG: hsa05016)
• Autophagy - animal (KEGG: hsa04140)
• Endocytosis (KEGG: hsa04144)
• Neurotrophin signaling pathway (KEGG: hsa04722)
• Apoptosis (KEGG: hsa04210)
• p53 signaling pathway (KEGG: hsa04115)
• Sphingolipid signaling pathway (KEGG: hsa04071)
• TNF signaling pathway (KEGG: hsa04668)
Protein Summary
Huntingtin is a large, predominantly cytoplasmic protein with a HEAT repeat domain that mediates protein-protein interactions. It serves as a scaffold for multiple complexes involved in vesicular trafficking, autophagy, and transcriptional regulation. The protein is cleaved by caspases and calpains, and the N-terminal fragment containing the polyglutamine tract is prone to aggregation when expanded. Huntingtin is essential for neuronal survival and function, and its mutant form leads to selective neurodegeneration in the striatum and cortex.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HTT Knockout HEK293 Cell Line | EDJ-KQ4863 | Human | 3064 | Details Get a Quote |
| HTT Knockout A-549 Cell Line | EDJ-KQ27640 | Human | 3064 | Details Get a Quote |
| HTT Knockout HCT 116 Cell Line | EDJ-KQ27641 | Human | 3064 | Details Get a Quote |
| HTT Knockout HeLa Cell Line | EDJ-KQ27642 | Human | 3064 | Details Get a Quote |
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