Transthyretin

Transthyretin (TTR or TBPA) is a

TTR was originally called prealbumin[5] (or thyroxine-binding prealbumin) because it migrated faster than albumin on electrophoresis gels. Prealbumin was felt to be a misleading name, it is not a synthetic precursor of albumin. The alternative name TTR was proposed by DeWitt Goodman in 1981.

Transthyretin protein is encoded by the TTR gene located on the 18th chromosome.

Binding affinities

It functions in concert with two other thyroid hormone-binding proteins in the serum:

In cerebrospinal fluid TTR is the primary carrier of T₄. TTR also acts as a carrier of retinol (vitamin A) through its association with retinol-binding protein (RBP) in the blood and the CSF. Less than 1% of TTR's T₄ binding sites are occupied in blood, which is taken advantage of below to prevent TTRs dissociation, misfolding and aggregation which leads to the degeneration of post-mitotic tissue.

Numerous other small molecules are known to bind in the thyroxine binding sites, including many natural products (such as resveratrol), drugs (tafamidis,^[6] diflunisal,^[7][8][9] and flufenamic acid),^[10] and toxicants (PCB^[11]).

Structure

TTR is a 55kDa homotetramer with a dimer of dimers quaternary structure that is synthesized in the

TTR misfolding and aggregation is known to be associated with amyloid diseases^[13] including wild-type transthyretin amyloidosis,^[14] hereditary transthyretin amyloidosis,^[15] familial amyloid polyneuropathy (FAP),^[16][17] and familial amyloid cardiomyopathy (FAC).^[18]

TTR tetramer dissociation is known to be rate-limiting for amyloid fibril formation.^[19][20][21] However, the monomer also must partially denature in order for TTR to be mis-assembly competent, leading to a variety of aggregate structures, including amyloid fibrils.^[22]

At least 114 disease-causing mutations in this gene have been discovered.^[23] While wild type TTR can dissociate, misfold, and aggregate, leading to SSA (senile systemic amyloidosis), point mutations within TTR are known to destabilize the tetramer composed of mutant and wild-type TTR subunits, facilitating more facile dissociation and/or misfolding and amyloidogenesis.^[24] A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly associated with FAP.^[25] A position 122 replacement of valine by isoleucine (TTR V122I) is carried by 3.9% of the African-American population, and is the most common cause of FAC.^[18] SSA is estimated to affect over 25% of the population over age 80.^[14] Severity of disease varies greatly by mutation, with some mutations causing disease in the first or second decade of life, and others being more benign. Deposition of TTR amyloid is generally observed extracellularly, although TTR deposits are also clearly observed within the cardiomyocytes of the heart.

Treatment of familial (hereditary) TTR amyloid disease has historically relied on liver transplantation as a crude form of gene therapy.^[26] Because TTR is primarily produced in the liver, replacement of a liver containing a mutant TTR gene with a normal gene is able to reduce the mutant TTR levels in the body to < 5% of pretransplant levels. Certain mutations, however, cause CNS amyloidosis, and due to their production by the choroid plexus, the CNS TTR amyloid diseases do not respond to gene therapy mediated by liver transplantation.

In 2011, the European Medicines Agency approved tafamidis (Vyndaqel) for the amelioration of FAP.^[6] Tafamidis kinetically stabilizes the TTR tetramer, preventing tetramer dissociation required for TTR amyloidogenesis and degradation of the autonomic nervous system^[27] and/or the peripheral nervous system and/or the heart.^[21]

TTR is also thought to have beneficial side effects, by binding to the infamous

Transthyretin is known to contain a Gla domain, and thus be dependent for production on post-translational modification requiring vitamin K, but the potential link between vitamin k status and thyroid function has not been explored.

Because transthyretin is made in part by the choroid plexus, it can be used as an immunohistochemical marker for choroid plexus papillomas as well as carcinomas.^{[citation needed]}

As of March 2015, there are two ongoing clinical trials undergoing recruitment in the United States and worldwide to evaluate potential treatments for TTR amyloidosis.^{[34][needs update]}

Interactions

Transthyretin has been shown to