TTR — Transthyretin

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TTR — Transthyretin

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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="

...

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

Factors Promoting Amyloidogenesis

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)

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)

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Related Entities

TTR

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slug	genes-ttr
kg_node_id	TTR
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-aa03a72fe7c6
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ttr'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

30%

Debates

0

Incoming

6

Outgoing

34

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

TTR — Transthyretin

TTR — Transthyretin

TTR — Transthyretin

TTR — Transthyretin

Introduction

Overview

Function

Normal Physiological Role

Tetramer Structure

Amyloidogenesis Mechanism

The Amyloid Cascade

Factors Promoting Amyloidogenesis

Key Amyloidogenic Mutations

Disease Associations

Hereditary Transthyretin Amyloidosis (hATTR)

Clinical Features

Geographic Distribution

Senile Systemic Amyloidosis (SSA)

Diagnosis

Genetic Testing

Biomarkers

Histopathology

Treatment

Disease-Modifying Therapies

1. Tetramer Stabilizers

2. RNA Interference (RNAi)

3. Antisense Oligonucleotides

4. Gene Editing

Symptomatic Management

Liver Transplant

Key Publications

External Links

See Also

Background

Brain Atlas Resources

Brain Atlas Resources

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion