Suppression of Transthyretin Synthesis by Antisense Oligonucleotides
Gilles Grateau, Robert A. Kyle, Martha Skinner in Amyloid and Amyloidosis, 2004
The only specific therapy for transthyretin (TTR) amyloidosis is liver transplantation (1). Essentially all plasma transthyretin is synthesized by the liver and transplantation results in disappearance of the variant TTR from the circulation. This has proven to be an effective therapy for many individuals with TTR amyloidosis, especially those with the Val30Met mutation. A significant number of patients, however, have progression of systemic amyloidosis after liver transplantation, and it has been hypothesized that this is the result of deposition of amyloid fibrils which are a product of normal TTR (2). In particular, patients with TTR Thr60Ala, Leu58His, and Cys10Arg have been observed to have progression of cardiac amyloidosis after liver transplantation. The increased ratio of normal to variant transthyretin in cardiac tissues obtained at autopsy from these patients is in agreement with this hypothesis. As an alternative therapy we have explored the use of antisense oligonucleotides (ASO) to TTR, modified to target the liver to decrease expression of TTR. To test this therapeutic option we have created a transgenic mouse model carrying the Ile84Ser variant gene of human TTR. TTR specific ASOs were then administered to mice, and TTR expression was measured in plasma and TTR mRNA levels in hepatic tissues.
Infiltrative Diseases
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
The transthyretin precursor protein is a carrier protein for thyroxine and holo-retinol binding protein and consists of four monomers that circulate as a tetramer. Transthyretin is mostly produced by the liver but can also be secreted by the choroid plexus and retinal pigmented epithelial cells. Destabilization of the tetramer can result in degradation into amyloidogenic monomers that misfold and self-aggregate to form ß-sheet-rich amyloid fibrils. ATTR amyloidosis is classified by the 127 amino acid sequence of the transthyretin gene, located on chromosome 18. If there is no mutation, then it is wild-type ATTR (wtATTR) amyloidosis, whereas hereditary ATTR (hATTR) is defined by the presence of a single amino acid mutation. Whereas the amino acid mutation accounts for the destabilization of the transthyretin tetramer, the instability of the wtATTR tetramer is attributed to the aging process.
Inherited Abnormalities in Thyroid Hormone Transport Proteins
Geraldo Medeiros-Neto, John Bruton Stanbury in Inherited Disorders of the Thyroid System, 2019
Transthyretin (TTR) is a 55-kDa protein consisting of four identical subunits each containing 127 amino acid residues. The tetramer is arranged so as to form a double trumpet-shaped channel where two binding sites for T4 are located. Usually only one T4 molecule is bound to TTR since the interaction of the T4 greatly decreases the binding affinity for the second binding site. The cDNA for human TTR has been cloned and the nucleotide sequence has been determined. It codes for a polypeptide consisting of 147 amino acids. The TTR gene appears to be relatively small in size (7.3 kb) and composed of 4 exons.10
Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR)
Published in Amyloid, 2018
Pooja Phull, Vaishali Sanchorawala, Lawreen H. Connors, Gheorghe Doros, Frederick L. Ruberg, John L. Berk, Shayna Sarosiek
Transthyretin is a protein produced by the liver that functions as a transporter for thyroxine (T4) and retinol [7]. Misfolding and fibril deposition of transthyretin may be caused by hereditary or genetic mutations (ATTRm) or by an acquired “wild-type” form of the disease (ATTRwt), previously referred to as senile systemic amyloidosis [6]. A common inherited cause of ATTRm cardiac amyloidosis is a valine-to-isoleucine substitution at position 122 of the TTR gene (referred to as ATTR V122I) [8,9]. The V122I mutation almost exclusively affects patients of African descent and appears in 3–4% of black Americans, with an age-dependent, variable penetrance [8,10]. A recent analysis of Afro-Caribbean patients >60 years of age with congestive heart failure demonstrated a prevalence of at least 12% for the V122I allele in that population [8].
Tafamidis concentration required for transthyretin stabilisation in cerebrospinal fluid
Published in Amyloid, 2023
Felix J. Tsai, Marcus Jaeger, Teresa Coelho, Evan T. Powers, Jeffery W. Kelly
Transthyretin is a 55-kDa tetrameric protein consisting of four β-sheet rich subunits, each comprising 127 amino acid residues [31]. The TTR tetramer binds and transports thyroxine and the holo-retinol binding protein. Binding of either slows TTR tetramer dissociation [31–34]. Following rate-limiting tetramer dissociation and partial monomer denaturation, TTR can aggregate into numerous non-native structures, including cross-β-sheet amyloid fibrils. The soluble non-native TTR structures seem to be the main driver of degenerative phenotypes [1,35]. Many pathogenic mutations destabilise the resulting TTR tetramers comprising mutant and WT TTR subunits, causing faster dissociation and leading to misfolding, aggregation, and initial degenerative phenotypes such as polyneuropathy (earlier called familial amyloid polyneuropathy (FAP)), or cardiomyopathy, or neuropathic leptomeningeal amyloidosis, depending on the identity of the TTR mutation [26]. Although more than 130 TTR mutations are associated with degenerative pathology, the most common mutation worldwide is Val30Met (V30M, p.TTRV50M). The V30M mutation causes a debilitating hereditary neuropathy involving sensory, motor, and autonomic nervous system dysfunction with many patients manifesting symptoms such as sensorimotor polyneuropathy; autonomic dysfunction; and gastrointestinal, heart, and kidney dysfunction [6–9].
Founder effect of the Glu89Gln TTR mutation in the Bulgarian population
Published in Amyloid, 2019
Andrey Kirov, Stayko Sarafov, Zornitza Pavlova, Tihomir Todorov, Teodora Chamova, Mariana Gospodinova, Ivailo Tournev, Vanyo Mitev, Albena Todorova
The disease is caused by extracellular deposition of amyloid fibrils composed of transthyretin. This is a 127 amino acid protein that is involved in the thyroxine and vitamin A transport in the blood plasma [4,5]. The native transthyretin is a homotetrameric complex, which can dissociate into monomers due to different factors. These monomeric forms are prone to aggregation into amyloid fibrils, causing several diseases including wild-type ATTR (ATTRwt) amyloidosis and hereditary transthyretin amyloidosis [6]. Transthyretin is encoded by the TTR gene (MIM *176300), located on chromosome 18 (18q11.2–12). It consists of 4 exons and up to date more than 120 pathogenic TTR genetic variants have been reported according to the online registry for mutations in hereditary amyloidosis [7].
Related Knowledge Centers
- Albumin
- Cerebrospinal Fluid
- Retinol
- Transport Protein
- Levothyroxine
- Blood Plasma
- Electrophoresis
- Choroid Plexus
- Retinol-Binding Protein
- Resveratrol