TTR

Official Full Name

transthyretin

Organism

Homo sapiens

GeneID

7276

Background

This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

Synonyms

CTS; TTN; ATTR; CTS1; PALB; TBPA; HEL111; HsT2651;

Bio Chemical Class

mRNA target

Protein Sequence

MASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE

Open

Disease

Amyloidosis, Amyloidosis

Approved Drug

4 +

Clinical Trial Drug

7 +

Discontinued Drug

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Detailed Information

The transthyretin protein gene (TTR) is located on the long arm of human chromosome 18 (18q12.1) and consists of four exons, encoding a monomeric protein of 127 amino acids. Under physiological conditions, four identical monomers associate through non-covalent interactions to form a stable homotetrameric structure with a molecular weight of approximately 55 kDa. This tetrameric conformation is essential for TTR's biological function and exhibits high solubility in both plasma and cerebrospinal fluid. TTR is primarily synthesized in the liver, with secondary expression in the choroid plexus and retinal pigment epithelium. Recent studies have also identified functional expression in skeletal muscle tissue. As a key transport protein, TTR specifically carries thyroid hormones (thyroxine T4 and triiodothyronine T3) in the circulation and participates in vitamin A transport by forming a complex with retinol-binding protein (RBP). Notably, TTR exhibits higher affinity for T4 than T3, carrying approximately 15–20% of circulating T4, while thyroxine-binding globulin (TBG) handles the majority of hormone transport. This specificity positions TTR as an essential regulator of thyroid hormone homeostasis and targeted tissue delivery.

Tetramer Stability and Pathogenic Misfolding

The stability of the TTR tetramer is critical for its physiological function. Under normal conditions, the tetramer exists in a dynamic equilibrium that allows reversible dissociation into monomers. This balance can be disrupted by gene mutations or age-related factors. More than 100 TTR mutations have been identified, with the most common pathogenic variants including Val30Met and Val122Ile. These mutations destabilize the tetramer, promoting monomer misfolding and aggregation into amyloid fibrils that deposit in the tissue interstitium, forming insoluble amyloid deposits. This process underlies hereditary transthyretin amyloidosis (hATTR). Age-related destabilization of wild-type TTR (wtTTR) can also lead to misfolding and amyloid formation in older adults, contributing to senile systemic amyloidosis, which primarily affects cardiac tissue.

Figure 1. Diagnostic algorithm for diagnosis of TTR cardiac amyloidosis. (Ruberg FL, et al., 2012)

Biological Function and Role in Tissue Regeneration

TTR's biological roles extend beyond hormone transport. It plays a significant role in skeletal muscle physiology. Studies using TTR knockout mouse models have shown that although overall body and muscle mass remain unchanged, muscle strength and exercise capacity are markedly reduced, indicating TTR's importance in muscle force generation and physical performance. Mechanistic investigations suggest that TTR regulates the proliferation of skeletal muscle stem cells (satellite cells), contributing to muscle regeneration. In models of skeletal muscle injury, TTR-deficient mice display reduced regenerated fiber area and a lower number of Pax7-positive satellite cells. Flow cytometry and EdU incorporation experiments confirm that TTR deletion directly impairs satellite cell proliferation. These findings suggest that TTR may influence tissue repair and regeneration through paracrine or endocrine mechanisms.

Pathological Mechanisms in Amyloidosis

Pathologically, TTR misfolding and amyloid deposition are central to systemic amyloidosis. Transthyretin amyloid cardiomyopathy (ATTR-CM) arises from tetramer dissociation, misfolded monomer aggregation, and deposition within the cardiac interstitium, leading to progressive myocardial stiffness and heart failure. ATTR-CM can be classified into wild-type (wtATTR-CM) and hereditary (hATTR-CM) forms, with wtATTR-CM primarily affecting older individuals. Amyloid deposition results in progressive cardiac hypertrophy, diastolic dysfunction, and arrhythmias, while hATTR-CM demonstrates more heterogeneous clinical manifestations, reflecting varying effects of different mutations on tetramer stability. The disease often progresses silently in its early stages, and late diagnosis complicates management.

Therapeutic Advances

Treatment strategies for ATTR-CM have evolved from organ transplantation to targeted pharmacotherapy. Liver transplantation, as the earliest approach, effectively replaces the source of mutant TTR in some hereditary cases, extending survival in selected patients. However, transplantation is limited by donor availability, lifelong immunosuppression, and incomplete disease control, especially in older individuals.

Modern therapies focus on three main mechanisms: reducing TTR synthesis, stabilizing the tetramer, and clearing deposited amyloid fibrils. Tetramer stabilizers, such as tafamidis, bind the T4 site to maintain tetramer integrity, slowing monomer dissociation and misfolding. While effective in delaying disease progression, these agents have limited benefit in advanced stages and cannot reverse existing deposits. Gene-silencing therapies represent a transformative approach. RNA interference drugs, such as Vutrisiran, inhibit hepatic TTR mRNA translation, reducing pathogenic protein production. These therapies have demonstrated improved survival and reduced cardiovascular events, emphasizing the potential of early intervention.

Gene-editing approaches offer a promising future direction. In vivo CRISPR-based therapies have shown the ability to achieve substantial reductions in circulating TTR after a single administration, potentially providing a "one-time, lifelong" treatment solution. Such strategies are under active clinical investigation and may expand applicability beyond cardiomyopathy to other TTR-related disorders.

Challenges and Future Directions

Despite progress, challenges remain. Early diagnosis remains difficult, limiting treatment efficacy. Therapeutic options are less effective in advanced heart failure, and long-term safety and resistance require ongoing evaluation. Future research will focus on developing non-invasive early diagnostic biomarkers, strategies to remove existing amyloid deposits, addressing neurological manifestations, and improving accessibility and cost-effectiveness of advanced therapies.

Reference

Ruberg FL, Maurer MS. Cardiac Amyloidosis Due to Transthyretin Protein: A Review. JAMA. 2024 Mar 5;331(9):778-791.
Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 4;126(10):1286-300.

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