Transthyretin
You don't need to be Editor-In-Chief to add or edit content to WikiDoc. You can begin to add to or edit text on this WikiDoc page by clicking on the edit button at the top of this page. Next enter or edit the information that you would like to appear here. Once you are done editing, scroll down and click the Save page button at the bottom of the page.
Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Transthyretin (TTR) is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4).
TTR was originally called prealbumin[1] because it ran faster than albumins on electrophoresis gels.
Binding affinities
It functions in concert with two other thyroid hormone binding proteins:
| Protein | Binding strength | Plasma concentration |
| thyroxine-binding globulin (TBG) | highest | lowest |
| transthyretin (TTR) | lower | higher |
| albumins | poorest | much higher |
TTR also acts as a carrier of retinol (vitamin A) through an association with retinol binding protein (RBP).
Numerous other small molecules are known to bind in the thyroxine binding sites, including many natural products (such as resveratrol), drugs (diflunisal, flufenamic acid), and toxins PCB. Since TTR binds promiscuously to many aromatic compounds, and generally does not bind T4 in serum, there is speculation that TTR's "true function" is to generally sweep up toxic and foreign compounds in the blood stream.
Structure
TTR is a 55 kDa homotetramer with a dimer of dimers configuration that is synthesized in the liver, choroid plexus and retinal pigment epithelium. Each monomer is a 127 residue polypeptide rich in beta sheet structure. Association of two monomers forms an extended beta sandwich. Further association of another identical set of monomers produces the homotetrameric structure. The two thyroxine binding sites per tetramer sit at the interface between the latter set of dimers.
Role in disease
TTR is known to be associated with the amyloid diseases senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC).
TTR is able to deposit as amyloid fibrils, causing neurodegeneration and organ failure. Both point mutations of TTR and wild-type protein are known to deposit as amyloid. A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly found in FAP. 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. SSA is estimated to effect over 25% of the population over age 80. Severity of disease varies greatly by mutation, with some mutations causing disease in the first or second decade of life, and others being completely benign. Deposition of TTR amyloid is extracellular. Treatment of TTR amyloid disease is currently limited to liver transplantation as a crude form of gene therapy. Because TTR is primarily produced in the liver, replacement of a liver containing a mutant TTR gene with a normal gene is able to replace the mutant TTR in the body. Certain mutations, however, have been found to have CNS involvement, and due to the blood brain barrier, do not respond to this therapy.
TTR is thought to have beneficial side, however, in binding to the infamous beta-amyloid protein, thereby preventing beta-amyloid's natural tendency to accumulate into the plaques associated with the early stages of Alzheimer's Disease. Preventing plaque formation is thought to enable a cell to rid itself of this otherwise toxic protein form and, thus, help prevent and maybe even treat the disease.
As with most amyloid diseases, it is still unclear whether the deposition of amyloid is the cause of the disease or a correlate of some upstream toxic process. With TTR, it is known that dissociation of the tetramer must occur, followed by misfolding events that ultimately result in amyloid fibrils. New research results point to the oligomers (consisting of max. 8 monomers) to generate the observed cell toxicity.
Transthyretin level in cerebrospinal fluid has also been found to be lower in patients with schizophrenia.[1] The reduced level of transthyretin in the CSF may indicate a lower thyroxine transport in brains of patients with schizophrenia.
Because transthyretin is made in part by the choroid plexus, it can be used as an immunohistochemical marker for choroid plexus papillomas.[citation needed]
Nutritional Assessment
In medicine, nutritional status (more specifically 'visceral protein status') can be assessed by measuring concentrations of prealbumin in the plasma. Although other transport proteins, such as Albumin or Transferrin, can also be used, prealbumin is a more reliable choice because of its shorter half life. [1]
| Protein | Half-Life (days) | Normal Levels | Malnutrition | ||
| mild | moderate | severe | |||
| Prealbumin | 2-4 | 15.7-29.6 mg/dL | 12-15 | 8-10 | <8 |
References
Further reading
- Sakaki Y, Yoshioka K, Tanahashi H, et al. (1990). "Human transthyretin (prealbumin) gene and molecular genetics of familial amyloidotic polyneuropathy.". Mol. Biol. Med. 6 (2): 161-8. PMID 2693890.
- Saraiva MJ (1995). "Transthyretin mutations in health and disease.". Hum. Mutat. 5 (3): 191-6. doi:10.1002/humu.1380050302. PMID 7599630.
- Ingenbleek Y, Young V (1994). "Transthyretin (prealbumin) in health and disease: nutritional implications.". Annu. Rev. Nutr. 14: 495-533. doi:10.1146/annurev.nu.14.070194.002431. PMID 7946531.
- Hesse A, Altland K, Linke RP, et al. (1994). "Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant.". British heart journal 70 (2): 111-5. PMID 8038017.
- Blanco-Jerez CR, Jiménez-Escrig A, Gobernado JM, et al. (1998). "Transthyretin Tyr77 familial amyloid polyneuropathy: a clinicopathological study of a large kindred.". Muscle Nerve 21 (11): 1478-85. PMID 9771673.
Proteins: albumin | |
|---|---|
| Egg white (albumEn) | Conalbumin - Ovalbumin - Avidin |
| Serum albumin | Human serum albumin - Bovine serum albumin - Prealbumin |
| Other | C-reactive protein - Lactalbumin - Parvalbumin - Ricin |
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
