| TTR — Transthyretin | |
|---|---|
| Symbol | TTR |
| Full Name | Transthyretin |
| Chromosome | 18q12.1 |
| NCBI Gene | 7276 |
| Ensembl | ENSG00000118271 |
| OMIM | 176300 |
| UniProt | P02766 |
| Diseases | Hereditary Transthyretin Amyloidosis, Senile Systemic Amyloidosis |
| Expression | Liver, Choroid plexus, Retinal pigment epithelium, Pancreas |
| Key Mutations | |
| Val30Met (most common worldwide) Val122Ile (common in African Americans) Thr60Ala (Appalachian variant) Leu58His (Maryland/German) >120 amyloidogenic mutations |
|
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.
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[1]. 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 and OMIM 176300.
Transthyretin is primarily synthesized in the liver (95%) and choroid plexus (5%), with minor production in the retinal pigment epithelium and pancreas[2]. 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:
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[3].
TTR amyloid formation follows a well-characterized pathway[4]:
| 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 |
Also known as familial amyloid polyneuropathy (FAP) when neuropathy predominates, or familial amyloid cardiomyopathy (FAC) when cardiac involvement is primary[5].
Peripheral neuropathy:
Cardiac involvement:
Central nervous system:
Other manifestations:
Wild-type (non-mutated) TTR can form amyloid deposits in elderly individuals (>80 years), predominantly affecting the heart and carpal tunnel[6]. Autopsy studies show:
These drugs bind to the TTR tetramer, preventing dissociation[7]:
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.
Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36(4):411-423. PMID: 17554796 ↩︎
Richardson SJ. Cell and molecular biology of the protein secretory pathway. Trends Biochem Sci. 2009;34(12):627-638. PMID: 19744834 ↩︎
Kelly JW. Alternative conformations of amyloidogenic proteins govern their aggregation. Proc Natl Acad Sci U S A. 1998;95(16):9307-9312. PMID: 9689085 ↩︎
Serpell CJ, Blake CC, Fraser PE. Structural basis of transthyretin amyloidogenesis. Cell Mol Life Sci. 2000;57(11):1577-1592. PMID: 11092451 ↩︎
Ando Y, Coelho T, Berk JL, et al. Guideline: amyloidosis. J Neurol Sci. 2013;332(1-2):41-50. PMID: 23747155 ↩︎
Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000298. PMID: 23557758 ↩︎
Bulawa CE, Connelly S, DeVit M, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that prevents the formation of amyloid fibrils. Proc Natl Acad Sci U S A. 2012;109(24):9629-9634. PMID: 22645358 ↩︎
Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. 2021;385(6):493-502. PMID: 34219115 ↩︎