TTR — Transthyretin
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TTR — Transthyretin</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TTR</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Transthyretin</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>18q12.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/7276" target="_blank">7276</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118271" target="_blank">ENSG00000118271</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/176300" target="_blank">176300</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P02766" target="_blank">P02766</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>Hereditary Transthyretin Amyloidosis, Senile Systemic Amyloidosis</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Liver, Choroid plexus, Retinal pigment epithelium, Pancreas</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Val30Met (most common worldwide)<br>Val122Ile (common in African Americans)<br>Thr60Ala (Appalachian variant)<br>Leu58His (Maryland/German)<br>>120 amyloidogenic mutations</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">35 edges</a></td>
</tr>
</table>
TTR — Transthyretin
Introduction
Ttr — Transthyretin is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
Mermaid diagram (expand to render)
Transthyretin (TTR) is a tetrameric transport protein encoded by the TTR gene on chromosome 18q12.1. Originally named for its ability to transport both thyroxine (T4) and retinol (via retinol-binding protein), TTR is now best known for its role in hereditary amyloidosis["@benson2007"]. Over 120 amyloidogenic mutations cause familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and leptomeningeal amyloidosis. The wild-type (wild-type) TTR protein can also form amyloid in late-onset senile systemic amyloidosis (SSA). The gene is catalogued as NCBI Gene ID [7276](https://www.ncbi.nlm.nih.gov/gene/7276) and OMIM [176300](https://omim.org/entry/176300).
Function
Normal Physiological Role
Transthyretin is primarily synthesized in the liver (95%) and choroid plexus (5%), with minor production in the retinal pigment epithelium and pancreas[@richardson2009]. Under normal conditions, TTR functions as:
Thyroxine (T4) transport: TTR binds T4 with low affinity but high specificity, accounting for ~5% of total T4 transport (thyroxine-binding globulin carries the majority)
Retinol transport: TTR forms a complex with retinol-binding protein (RBP), facilitating vitamin A transport to tissues
Homeostatic functions:
- Maintains cerebrospinal fluid composition (choroid plexus production)
- May have protective effects against oxidative stress
- Potential role in neuroprotection through thyroxine delivery to the brain
Tetramer Structure
Native TTR exists as a homotetramer (127 aa subunits), which is the key structural feature that determines its stability. The tetramer dissociates into monomers under certain conditions, and monomers can misfold to form amyloid fibrils[@kelly1998].
- Tetramer molecular weight: ~55 kDa
- Each subunit: ~14 kDa, containing an 8-stranded β-sheet
- Stability determinants: Dimer-dimer interface interactions
Amyloidogenesis Mechanism
The Amyloid Cascade
TTR amyloid formation follows a well-characterized pathway[@serpell2000]:
Tetramer dissociation: The native tetramer slowly dissociates into monomers (rate-limiting step)
Partial unfolding: Monomers undergo conformational changes, exposing hydrophobic regions
Oligomerization: Unfolded monomers aggregate into soluble oligomers (toxic species)
Fibril formation: Oligomers assemble into insoluble amyloid fibrils
Tissue deposition: Fibrils accumulate as extracellular amyloid deposits
- Mutation: Certain amino acid substitutions destabilize the tetramer (e.g., Val30Met)
- Age: Wild-type TTR becomes more amyloidogenic with age
- Oxidative stress: Post-translational modifications (TTR oxidation)
- Proteolytic cleavage: Truncated TTR fragments seed amyloid formation
- pH lowering: Acidic environments promote dissociation
Key Amyloidogenic Mutations
| Mutation | Typical Onset | Primary Phenotype | Prevalence |
|----------|---------------|-------------------|------------|
| Val30Met | 30-40 years | Polyneuropathy | Most common worldwide |
| Val122Ile | 60-70 years | Cardiomyopathy | Common in African ancestry |
| Thr60Ala | 50-60 years | Mixed (neuropathy + cardiomyopathy) | Appalachian population |
| Glu89Gln | 40-50 years | Leptomeningeal | Portuguese families |
| Ile107Phe | 50-60 years | Cardiomyopathy | Danish population |
Disease Associations
Hereditary Transthyretin Amyloidosis (hATTR)
Also known as familial amyloid polyneuropathy (FAP) when neuropathy predominates, or familial amyloid cardiomyopathy (FAC) when cardiac involvement is primary[@ando2013].
Clinical Features
Peripheral neuropathy:
- Small-fiber neuropathy (pain, temperature, autonomic dysfunction)
- Progressive sensory loss in lower extremities
- Motor weakness later in disease course
- Autonomic neuropathy (orthostatic hypotension, gastrointestinal dysmotility)
Cardiac involvement:
- Restrictive cardiomyopathy
- Conduction system disease (AV block, bundle branch block)
- Heart failure with preserved ejection fraction
- Atrial arrhythmias
Central nervous system:
- Leptomeningeal amyloidosis (rare, especially with Glu89Gln)
- Cerebral amyloid angiopathy
- Hydrocephalus
Other manifestations:
- Vitreous amyloidosis
- Renal amyloidosis
- carpal tunnel syndrome
Geographic Distribution
- Portugal: Val30Met, prevalence ~1:538 in northern regions
- Japan: Val30Met, discovered in 1952
- Sweden: Val30Met, endemic in northern regions
- Africa: High Val122Ile carrier frequency (~3-4%)
Senile Systemic Amyloidosis (SSA)
Wild-type (non-mutated) TTR can form amyloid deposits in elderly individuals (>80 years), predominantly affecting the heart and carpal tunnel[@pinney2013]. Autopsy studies show:
- Cardiac TTR deposits in 20-25% of individuals over 80
- Carpal tunnel syndrome due to TTR deposits in up to 30% of elderly
Diagnosis
Genetic Testing
- Targeted sequencing: Identify pathogenic variants in TTR gene
- Mass spectrometry: Detect TTR protein in amyloid deposits
- Newborn screening: Some populations screen for Val30Met
Biomarkers
- Cardiac: Troponin, NT-proBNP, echocardiogram/MRI with late gadolinium enhancement
- Neurologic: Nerve conduction studies, skin biopsy for intraepidermal nerve fiber density
- Imaging: 99mTc-PYP scan for cardiac amyloid (also binds ATTR)
Histopathology
- Congo red staining: Apple-green birefringence under polarized light
- Immunohistochemistry: Anti-TTR antibodies
- Mass spectrometry-based proteomics: Definitive typing of amyloid
Treatment
Disease-Modifying Therapies
1. Tetramer Stabilizers
These drugs bind to the TTR tetramer, preventing dissociation[@bulawa2012]:
- Tafamidis (Vyndaqel/Vyndamax): FDA-approved for ATTR cardiomyopathy; binds T4-binding site, stabilizes tetramer
- Diflunisal: NSAID that stabilizes TTR; FDA-approved for pain but used off-label for ATTR polyneuropathy
- Acoramidis: Next-generation stabilizer showing promise in clinical trials
2. RNA Interference (RNAi)
- Patisiran (Onpattro): siRNA targeting TTR mRNA; reduces hepatic TTR production by 87%
- Vutrisiran (Amvuttra): Subcutaneous RNAi therapeutic; similar efficacy to patisiran
3. Antisense Oligonucleotides
- Inotersen (Tegsedi): Antisense oligonucleotide reducing hepatic TTR production
4. Gene Editing
- NTLA-2001 (CRISPR-Cas9): In vivo gene editing to knockout TTR gene; Phase 1 trials show 90%+ reduction in serum TTR[@gillmore2021]
Symptomatic Management
- Neuropathic pain: Gabapentin, pregabalin, duloxetine
- Autonomic dysfunction: Midodrine for orthostasis, fludrocortisone
- Heart failure: Diuretics, rate control for AF, pacemaker if conduction disease
- Carpal tunnel: Surgical release
Liver Transplant
- Rationale: Eliminates major source of mutant TTR (liver)
- Outcomes: Best for early-stage Val30Met patients; less effective for Val122Ile or late presentation
Key Publications
[Transthyretin mutations in health and disease](https://doi.org/10.1002/humu.20190). Human Mutation, 2005.
[Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy](https://doi.org/10.3389/fneur.2023.1242815). Frontiers in Neurology, 2023.
[Patisiran for hereditary transthyretin amyloidosis](https://doi.org/10.1056/NEJMoa1716153). New England Journal of Medicine, 2018.
[Inotersen for hereditary transthyretin amyloidosis with polyneuropathy](https://doi.org/10.1056/NEJMoa1716793). New England Journal of Medicine, 2018.
[CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis](https://doi.org/10.1056/NEJMoa2107454). New England Journal of Medicine, 2021.
[Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy](https://doi.org/10.1056/NEJMoa1805689). New England Journal of Medicine, 2018.
[ATTR Amyloidosis: Current and emerging therapies](https://doi.org/10.1038/s41582-022-00706-w). Nature Reviews Neurology, 2022.
[Epidemiology of hereditary transthyretin amyloidosis](https://doi.org/10.1111/joim.13363). Journal of Internal Medicine, 2022.
[Mechanisms of TTR amyloidogenesis and therapeutic strategies](https://doi.org/10.1016/j.jmb.2021.166892). Journal of Molecular Biology, 2021.
[Cardiac amyloidosis: advances in diagnosis and treatment](https://doi.org/10.1016/j.jacc.2021.09.014). Journal of the American College of Cardiology, 2021.
External Links
- NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/7276](https://www.ncbi.nlm.nih.gov/gene/7276)
- Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118271](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118271)
- OMIM: [https://omim.org/entry/176300](https://omim.org/entry/176300)
- UniProt: [https://www.uniprot.org/uniprot/P02766](https://www.uniprot.org/uniprot/P02766)
- Amyloidosis Research Consortium: [https://arci.org](https://arci.org)
- ATTRwt Amyloidosis Foundation: [https://www.attrwt.org](https://www.attrwt.org)
See Also
- [Hereditary Transthyretin Amyloidosis](/diseases/hereditary-transthyretin-amyloidosis)
- [Amyloid Cascade](/mechanisms/amyloid-cascade)
- [Peripheral Neuropathy](/contactin-1---biomarker-for-peripheral-neuropathy)
- [Cardiac Amyloidosis](/diseases/cardiac-amyloidosis)
- [Genes Index](/genes)
- [Proteins Index](/proteins)
Background
The study of Ttr — Transthyretin has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Brain Atlas Resources
- [Allen Human Brain Atlas - TTR Expression](https://human.brain-map.org/microarray/search/show?search_term=TTR): Gene expression data from the Allen Human Brain Atlas
- [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/static/download.html): Developmental expression data for TTR
Brain Atlas Resources
- [Allen Human Brain Atlas - TTR Expression](https://human.brain-map.org/microarray/search/show?search_term=TTR): Gene expression data from the Allen Human Brain Atlas
- [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/static/download.html): Developmental expression data for TTR
Brain Atlas Resources
- [Allen Human Brain Atlas - TTR Expression](https://human.brain-map.org/microarray/search/show?search_term=TTR): Gene expression data from the Allen Human Brain Atlas
- [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/static/download.html): Developmental expression data for TTR
References
[Benson MD, Kincaid JC, The molecular biology and clinical features of amyloid neuropathy (2007)](https://pubmed.ncbi.nlm.nih.gov/17554796/)
[Richardson SJ, Cell and molecular biology of the protein secretory pathway (2009)](https://pubmed.ncbi.nlm.nih.gov/19744834/)
[Kelly JW, Alternative conformations of amyloidogenic proteins govern their aggregation (1998)](https://pubmed.ncbi.nlm.nih.gov/9689085/)
[Serpell CJ, Blake CC, Fraser PE, Structural basis of transthyretin amyloidogenesis (2000)](https://pubmed.ncbi.nlm.nih.gov/11092451/)
[Ando Y, Coelho T, Berk JL, et al, Guideline: amyloidosis (2013)](https://pubmed.ncbi.nlm.nih.gov/23747155/)
[Pinney JH, Whelan CJ, Petrie A, et al, Senile systemic amyloidosis: clinical features at presentation and outcome (2013)](https://pubmed.ncbi.nlm.nih.gov/23557758/)
[Bulawa CE, Connelly S, DeVit M, et al, Tafamidis, a potent and selective transthyretin kinetic stabilizer that prevents the formation of amyloid fibrils (2012)](https://pubmed.ncbi.nlm.nih.gov/22645358/)
[Gillmore JD, Gane E, Taubel J, et al, CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis (2021)](https://pubmed.ncbi.nlm.nih.gov/34219115/)Pathway Diagram
The following diagram shows the key molecular relationships involving TTR — Transthyretin discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)