Disease relevance of TTR

• The Val30 --> Met30 (V30M) TTR mutation is the most prevalent cause of familial amyloid polyneuropathy in heterozygotes, whereas a Thr119 --> Met119 (T119M) mutation on the second TTR allele protects V30M carriers from disease [1].
• In a family expressing euthyroid hyperthyroxinemia, an increased association of plasma thyroxine (T4) with transthyretin (TTR) is transmitted by autosomal dominant inheritance and is secondary to a mutant TTR molecule with increased affinity for T4 [2].
• The most frequent form of inherited amyloidoses is associated with mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex [3].
• In transthyretin (TTR) a new mutation (TTR-Thr45) has been identified in a patient with familial amyloidosis characterized clinically by prominent cardiomyopathy and the absence of peripheral neuropathy [4].
• The Ile-84-->Ser mutation and several other point mutations in TTR are associated with familial amyloidotic polyneuropathy, which is characterized by extracellular depositions of amyloid fibrils mainly consisting of mutated TTRs [5].
• Since the TTR monomeric forms are the results of different oxidizing reactions, we hypothesize that the higher oxidative stress in preeclampsia is the major destabilizing factor of the TTR functional dimeric form in the preeclamptic women [6].

Psychiatry related information on TTR

• CNS involvement is rare in systemic amyloidoses due to transthyretin (TTR) mutation and manifests as a combination of dementia, seizures, and myelopathy [7].
• Serum concentrations of IgG, IgA, IgM, haptoglobin, transferrin, prealbumin and albumin quantitated nephelometrically in 22 patients with Alzheimer's disease (AD), 29 patients with multi-infarct dementia (MID) and their age-matched controls were normal [8].
• We measured the levels of two beta-amyloid (Abeta)-sequestering proteins, apolipoprotein (Apo) E and transthyretin (TTR), in ventricular human cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients and controls in relation to brain histological findings [9].
• Therefore we quantified TTR in CSF and serum samples from 8 patients with early onset AD (EAD), 18 patients with late onset AD (LAD), 8 patients with vascular dementia (VAD) and 18 healthy individuals using a nephelometric method [10].
• An association study between the transthyretin (TTR) gene and mental retardation [11].

High impact information on TTR

• We recommend immunohistochemical staining of myocardial tissue for prealbumin in patients with biopsy-proved cardiac amyloid in whom no monoclonal immunoglobulin light chain is detectable in the serum or urine [12].
• We diagnosed senile systemic amyloidosis causing cardiac dysfunction in five men (57 to 72 years old) by using antiserum to prealbumin in myocardial biopsy tissue [12].
• Familial euthyroid hyperthyroxinemia resulting from increased thyroxine binding to thyroxine-binding prealbumin [13].
• The concentrations of plasma retinol-binding protein and prealbumin were, in contrast, non to retinol-binding protein [14].
• Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor [15]?

Chemical compound and disease context of TTR

• Some of the OH-PCBs displace thyroid hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR is the major T4 transporter [16].
• Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T(4)) and retinol-binding protein, are deposited in tissues [17].
• In this paper we demonstrate a stabilizing effect of sulfite on TTR tetramers from a familial amyloidotic polyneuropathy (FAP) patient homozygous for the most-common amyloidogenic TTR-V30 M mutation [18].
• A 40-year-old man presented with initial symptoms of syncope caused by restrictive cardiomyopathy and autonomic nervous system impairment, but it was confirmed that he had a novel transthyretin (TTR) variant, aspartic acid-18 glutamic acid (Glu), and a de novo gene mutation [19].
• A new TTR genetic variant is reported in a German family where the index patient presented at the age of 63 with anginal pain and arrhythmia [20].

Biological context of TTR

• Exons 2, 3, and 4 (representing greater than 97% of the coding sequence) of the TTR gene of DNA prepared from the propositus' peripheral blood leukocytes were amplified using the polymerase chain reaction (PCR) and were sequenced after subcloning [2].
• So far, more than 40 distinct amino acid substitutions distributed throughout the TTR sequence over 30 positions have been found to be correlated with an increased amyloidogenicity of TTR [3].
• This change can be explained by a single base change of adenine for guanine in the Ala-45 codon and was demonstrated directly by DNA sequence analysis of PCR-amplified exon 2 of the TTR gene; allele-specific oligonucleotide hybridization both in the patient and in fixed heart tissue from his aunt confirmed the base change [4].
• Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors [21].
• Two independent and equivalent RBP binding sites on recombinant normal TTR are characterized by a dissociation constant of about 0.4 microM [5].

Anatomical context of TTR

• The latter two diseases are associated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of the lysosome [22].
• The transthyretin (TTR) amyloidoses are human diseases in which the misfolded TTR protein aggregates in tissues with subsequent visceral, peripheral, and autonomic nerve dysfunction [23].
• Transthyretin (TTR) is a tetrameric protein synthesized mainly by the liver and the choroid plexus, from where it is secreted into the plasma and the cerebrospinal fluid, respectively [24].
• TTR is one of three specific carrier proteins involved in the transport of both thyroid hormones and of retinol through the mediation of RBP [25].
• To evaluate the importance of megalin for renal uptake of TTR, we performed binding/uptake assays using immortalized rat yolk sac cells with high expression levels of megalin [26].

Associations of TTR with chemical compounds

• In 50% of clones amplified from exon 4, a substitution of adenine (ACC) for guanine (GCC) in codon 109 resulted in the replacement of threonine-for-alanine, a mutation confirmed by amino acid sequencing of tryptic peptides derived from purified plasma TTR [2].
• Conformational stability and unfolding behavior of the Ile-20 monomer in urea gradients was found to be almost indistinguishable from that of wild-type TTR [3].
• Here we demonstrate that flufenamic acid (Flu) inhibits the conformational changes of TTR associated with amyloid fibril formation [22].
• In the present study we observed that TTR, the transporter of both T(4) and retinol-binding protein, binds to megalin, the multiligand receptor expressed on the luminal surface of various epithelia including the renal proximal tubules [26].
• Transthyretin (TTR) is a plasma homotetrameric protein that acts physiologically as a transporter of thyroxine (T(4)) and retinol, in the latter case through binding to retinol-binding protein (RBP) [27].
• It has been suggested that amyloidogenicity may be conferred to wild-type TTR (the form deposited in SSA) by chemical modification of the lone cysteine residue (Cys(10)) through mixed disulfide bonds [28].

Physical interactions of TTR

• A fraction of plasma TTR is carried in high density lipoproteins by binding to apolipoprotein AI (apoA-I) [27].
• Secondly, we found that the truncation resulting in RBP2 does not alter its binding properties for retinol nor those of holo-RBP2 for TTR [29].
• The crystal structure of the bipartite DNA-binding domain of HNF-6alpha complexed with the HNF-6-binding site of the TTR promoter revealed the DNA recognition mechanism of this protein [30].
• Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases [31].
• We then used a synthetic flavonoid (EMD) that competitively inhibits binding of T4 to serum TTR and transiently increases serum free T4 to determine the role of choroid plexus TTR and CSF TTR in the transport of T4 from serum to brain [32].

Co-localisations of TTR

• ApoAI and TTR co-localized in amyloid deposits as demonstrated by immunohistochemistry [33].

Regulatory relationships of TTR

• Interestingly, 2,4-DNP not only binds to TTR at acidic pH but also inhibits amyloid fibril formation as shown by the light scattering and Congo red-binding assay [34].
• A polymerase chain reaction-induced mutation restriction analysis with a mismatched sense primer demonstrated that he was heterozygous for TTR Glu 18 [19].
• While TTR expressed alone was not retained intracellularly, TTR was retained in vitamin A-deficient cells when co-expressed with RBP [35].

Other interactions of TTR

• Serum prealbumin, retinol-binding protein, transferrin, and albumin levels in patients with large bowel cancer [36].
• A nearly negligible affinity of the recombinant Ser-84 TTR for RBP was found [5].
• Taken together, the present data indicate that TTR represents a novel megalin ligand of importance in the thyroid hormone homeostasis [26].
• We found that calnexin, an ER integral membrane protein which functions as a chaperone, coprecipitates with RBP and TTR when cell lysis and immunoprecipitation are performed under mild conditions (1% Triton X-100) [37].
• These in vivo and in vitro biochemical experiments showed that TTR bound Abeta1-42 preferentially, and Abeta1-40 only to a limited extent, to form TTR-monomer and -dimer-Abeta complexes in the normal human kidney [38].
• BiP protects the TTR variants from immediate degradation [39].

Analytical, diagnostic and therapeutic context of TTR

• Incubation of TTR under the conditions of the cell assay and analysis by size-exclusion chromatography and SDS/PAGE reveal that monomeric TTR or relatively small, rapidly formed aggregates of a maximum size of six subunits were the major cytotoxic species [23].
• Comparative peptide mapping by high-performance liquid chromatography of the patient's plasma TTR together with normal TTR showed the presence of an abnormal tryptic peptide in the patient's TTR [4].
• In cell culture, different TTR mutations presented different levels of cell association and degradation, suggesting that the structure of TTR is important for megalin recognition [26].
• These TTR variants were previously detected by isoelectric focusing (IEF); one is a neutral TTR variant and the other one is basic [40].
• A variant found in nonamyloid group was sequenced by HPLC/ESI tandem MS using peptides obtained by protelytic digestion of TTR and by DNA analysis [41].

References