TTR Gene (Transthyretin): Function, Associated Diseases, and Clinical Significance
Explore the TTR gene, its role in transport proteins, amyloidosis-related mutations, and clinical implications.
Gene Information Card
| Symbol | TTR |
|---|---|
| Full Name | Transthyretin |
| Gene Type | Protein coding |
| Chromosomal Location | 18q12.1 |
| NCBI Gene ID | 7276 ncbi.nlm.nih.gov/gene/7276 |
| Ensembl ID | ENSG00000118271 |
| UniProt ID | P02766 |
| OMIM ID | 176300 |
| HGNC ID | 12405 |
| Aliases | ATTR, CTS, CTS1, PALB, TBPA |
Description
The TTR gene encodes transthyretin, a serum and cerebrospinal fluid protein that transports thyroxine (T4) and retinol (via retinol-binding protein). It is primarily synthesized in the liver, choroid plexus, and retina. Mutations in TTR can lead to misfolding and aggregation of the protein, causing systemic or central nervous system amyloidosis. The gene is also implicated in senile systemic amyloidosis and familial amyloid polyneuropathy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hereditary Transthyretin Amyloidosis (ATTR) | Missense mutations destabilize the tetrameric structure, leading to dissociation, misfolding, and extracellular amyloid deposition in peripheral nerves, heart, and other tissues. | ClinVar, OMIM |
| Familial Amyloid Polyneuropathy (FAP) | Specific mutations (e.g., Val30Met) cause early-onset peripheral neuropathy due to amyloid deposition in nerves. | OMIM, ClinVar |
| Familial Amyloid Cardiomyopathy (FAC) | Mutations such as Val122Ile lead to cardiac amyloid deposition, causing restrictive cardiomyopathy. | ClinVar, OMIM |
| Senile Systemic Amyloidosis (SSA) | Wild-type TTR can misfold with aging, leading to amyloid deposits in the heart and other tissues. | OMIM, PubMed |
| Leptomeningeal Amyloidosis | Certain mutations (e.g., Asp18Gly) cause amyloid deposition in the central nervous system, leading to stroke-like episodes and dementia. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | High (nTPM ~ 1000) | Primary site of synthesis |
| Choroid Plexus | High (nTPM ~ 500) | Synthesis in brain |
| Retina | Moderate (nTPM ~ 100) | Produced by retinal pigment epithelium |
| Pancreas | Low (nTPM ~ 10) | Minor expression |
| Kidney | Low (nTPM ~ 5) | Minor expression |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver) | High | Hepatocyte cell line |
| ARPE-19 (retinal pigment epithelium) | Moderate | Retinal cell line |
| U87 (glioblastoma) | Low | Brain cell line |
| HeLa (cervical) | Low | Non-specific expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Val30Met | Missense | Most common in FAP; high frequency in Portugal, Japan, Sweden | Destabilizes tetramer, promotes amyloid formation |
| Val122Ile | Missense | Common in African-American population; ~3-4% carrier frequency | Cardiac amyloidosis, late-onset |
| Thr60Ala | Missense | Common in Irish/UK population | Mixed neuropathy and cardiomyopathy |
| Asp18Gly | Missense | Rare | Leptomeningeal amyloidosis |
| Ser77Tyr | Missense | Rare | Cardiomyopathy and neuropathy |
Mutation functional classification
Loss of Function (LOF)
Not applicable; TTR mutations are not associated with loss of function. The protein's normal transport function is largely preserved, but pathogenic variants cause toxic gain-of-function via amyloid deposition.
Gain of Function (GOF)
Most TTR mutations are gain-of-function, leading to misfolding and aggregation of the protein into amyloid fibrils, which deposit in tissues and cause organ damage.
Dominant Negative (DN)
Some mutations may exert a dominant-negative effect by incorporating mutant monomers into tetramers, destabilizing the complex and promoting dissociation, but the primary mechanism is gain-of-function.
View complete mutation data：
Gene Ontology (GO)
| • serine-type endopeptidase inhibitor activity (GO:0004867) | • thyroid hormone binding (GO:0005496) |
| • protein binding (GO:0005515) | • extracellular region (GO:0005576) |
| • extracellular space (GO:0005615) | • cytoplasm (GO:0005737) |
| • cytosol (GO:0005829) | • transport (GO:0006810) |
| • visual perception (GO:0007601) | • oxidoreductase activity (GO:0016491) |
| • anchored component of external side of plasma membrane (GO:0031362) | • identical protein binding (GO:0042802) |
| • protein homodimerization activity (GO:0042803) | • protein heterodimerization activity (GO:0046982) |
| • defense response to Gram-negative bacterium (GO:0050829) | • defense response to fungus (GO:0050832) |
| • extracellular exosome (GO:0070062) |
Pathways
• Thyroid hormone synthesis and transport
• Retinol metabolism and transport
• Amyloid fiber formation (pathological)
• Protein misfolding and aggregation (pathological)
Protein Summary
Transthyretin (TTR) is a 127-amino acid protein that forms a homotetramer in plasma and cerebrospinal fluid. Each monomer contains a beta-sheet-rich structure that binds thyroxine (T4) and retinol-binding protein (RBP). The protein is primarily synthesized by the liver, choroid plexus, and retina. Under physiological conditions, TTR transports thyroid hormones and vitamin A. Pathogenic mutations destabilize the tetramer, leading to dissociation into monomers that misfold and aggregate into amyloid fibrils. These fibrils deposit in peripheral nerves, heart, and other tissues, causing progressive and often fatal amyloid diseases. Therapeutic strategies include stabilizing the tetramer (e.g., tafamidis) or silencing TTR gene expression (e.g., patisiran, inotersen).
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TTR Knockout HEK293 Cell Line | EDJ-KQ1959 | Human | 7276 | Details Get a Quote |
| TTR Knockout HeLa Cell Line | EDJ-KQ54704 | Human | 7276 | Details Get a Quote |
| TTR Knockout A-549 Cell Line | EDJ-KQ63192 | Human | 7276 | Details Get a Quote |
| TTR Knockout HCT 116 Cell Line | EDJ-KQ71663 | Human | 7276 | Details Get a Quote |
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