Affinage

TTR

Transthyretin · UniProt P02766

Round 2 corrected
Length
147 aa
Mass
15.9 kDa
Annotated
2026-04-28
130 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TTR (transthyretin) is a β-strand-rich homo-tetrameric transport protein, synthesized primarily by the liver and choroid plexus, that carries thyroxine (T4) via two binding sites at its dimer–dimer interface and retinol via association with retinol-binding protein (RBP) on both faces of the tetramer (PMID:671542, PMID:7754382). Tetramer dissociation into non-native monomers is the rate-limiting step in amyloidogenesis: monomers and small oligomers (<100 kDa) constitute the principal cytotoxic species, while mature fibrils are comparatively inert (PMID:14981241). Kinetic stabilization of the tetramer—achieved pharmacologically by small molecules occupying the T4-binding channels or genetically by the trans-suppressor mutation T119M—raises the dissociation barrier and prevents amyloid formation, providing the mechanistic basis for therapy in both hereditary (Val30Met) and wild-type TTR amyloidosis (PMID:12560553, PMID:11577236). Missense mutations in TTR (notably Val30Met) cause familial amyloidotic polyneuropathy, whereas wild-type TTR forms amyloid fibrils in senile systemic amyloidosis without any coding mutation (PMID:6651852, PMID:2320592).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1974 High

    Determination of the complete primary structure of human TTR established it as a homo-tetramer of identical subunits, enabling all subsequent structure–function work.

    Evidence Protein sequencing of cyanogen bromide and tryptic peptides from plasma prealbumin

    PMID:4607556

    Open questions at the time
    • No tertiary or quaternary structural detail yet available
    • No information on ligand binding sites
  2. 1978 High

    The 1.8 Å crystal structure revealed a β-sheet-rich tetramer with two T4-binding sites at the dimer–dimer interface, defining the architectural framework for understanding both transport function and amyloidogenesis.

    Evidence X-ray crystallography with Fourier refinement at 1.8 Å resolution

    PMID:671542

    Open questions at the time
    • RBP binding geometry unknown
    • No structural basis for why TTR misfolds
  3. 1983 High

    Identification of the Val30Met substitution in amyloid fibrils from FAP patients established TTR as the direct precursor of hereditary amyloid, linking a specific point mutation to systemic amyloidosis.

    Evidence Peptide mapping and sequence analysis of amyloid fibril protein versus normal prealbumin

    PMID:6651852

    Open questions at the time
    • Whether wild-type TTR can also form amyloid was unknown
    • Mechanism by which Val30Met destabilizes TTR not defined
  4. 1986 High

    Demonstration that TTR mRNA is synthesized specifically by choroid plexus epithelial cells in the CNS established this tissue as the source of CSF TTR, distinct from hepatic production.

    Evidence Northern blot, in situ hybridization, immunocytochemistry, and in vitro translation in rat and human brain tissue

    PMID:3714052

    Open questions at the time
    • Regulatory elements controlling choroid plexus versus hepatic expression not yet dissected
    • Neuronal expression not yet identified
  5. 1990 High

    Sequencing of amyloid fibrils from senile systemic amyloidosis patients revealed wild-type TTR as the precursor, proving that amyloidogenesis does not require a coding mutation and implicating age-related destabilization.

    Evidence Protein sequencing of fibril material from SSA patients compared with normal TTR

    PMID:2320592

    Open questions at the time
    • Factors that drive wild-type TTR destabilization with age remain undefined
    • No structural comparison of wild-type versus mutant fibril architecture
  6. 1991 High

    Systematic mutagenesis and in vivo footprinting of the TTR promoter identified an essential HNF-3 binding site and revealed liver-specific transcription factor occupancy, explaining tissue-restricted expression.

    Evidence Site-directed mutagenesis with reporter assays in hepatoma cells; in vivo genomic footprinting in mouse liver

    PMID:1870969 PMID:1989908

    Open questions at the time
    • Choroid plexus and neuronal promoter regulation not yet addressed
    • Enhancer–promoter communication mechanism not resolved
  7. 1995 High

    The crystal structure of the TTR–RBP complex showed two RBP molecules bind the same TTR dimer face, defining the molecular basis for retinol transport and explaining the 2:1 RBP:TTR stoichiometry.

    Evidence X-ray crystallography of the TTR–RBP co-crystal at 3.1 Å resolution

    PMID:7754382

    Open questions at the time
    • Mechanism of retinol transfer from RBP–TTR complex to target cells not defined
    • Whether RBP binding modulates TTR stability unknown
  8. 2001 High

    Reconstitution of mixed V30M/T119M tetramers demonstrated that incorporation of T119M subunits strongly stabilizes the tetramer against dissociation, providing the molecular mechanism for intragenic trans-suppression of FAP.

    Evidence Biophysical analysis of reconstituted mixed tetramers, dissociation assays under denaturing conditions, analytical ultracentrifugation

    PMID:11577236

    Open questions at the time
    • Whether other trans-suppressor variants act by the same mechanism was only partly addressed
    • In vivo kinetics of mixed tetramer formation not measured
  9. 2003 High

    Kinetic (not thermodynamic) stabilization of the TTR tetramer was established as the operative mechanism by which both the T119M mutation and small-molecule inhibitors prevent amyloidogenesis, validating kinetic stabilization as a therapeutic strategy.

    Evidence In vitro rate constant measurements for tetramer dissociation comparing small molecules and T119M variant

    PMID:12560553

    Open questions at the time
    • In vivo pharmacokinetic validation of small-molecule stabilizers not shown here
    • Whether kinetic stabilization fully prevents oligomer toxicity in vivo unknown
  10. 2004 High

    Size-fractionation experiments identified monomers and small oligomers (<100 kDa) as the cytotoxic species to neural cells, while mature fibrils and large aggregates were non-toxic, shifting the pathogenic model from fibril deposition to pre-fibrillar intermediates.

    Evidence Cell viability assays with SEC-fractionated TTR quaternary structures and rescue by tetramer-stabilizing small molecules

    PMID:14981241

    Open questions at the time
    • Specific receptors or cellular pathways mediating oligomer toxicity not identified
    • In vivo relevance of size fractions not directly tested
  11. 2014 High

    HSF1 was shown to directly occupy heat shock elements in the TTR promoter in neurons but not in hepatocytes or cardiomyocytes, revealing a cell-type-specific transcriptional circuit for neuronal TTR upregulation distinct from hepatic HNF-driven expression.

    Evidence Chromatin immunoprecipitation in SH-SY5Y cells, primary hippocampal neurons, and APP23 mouse hippocampus; gain- and loss-of-function for HSF1

    PMID:24849358

    Open questions at the time
    • Functional consequence of neuronal TTR upregulation for neuroprotection not causally demonstrated
    • Other neuron-specific co-regulators not identified
  12. 2016 Medium

    TTR V30M aggregates impair late-stage autophagic flux (p62 accumulation) in cell and transgenic mouse models, and pharmacological agents (curcumin, TUDCA) rescue this defect, implicating autophagy dysfunction as a secondary pathogenic mechanism downstream of TTR aggregation.

    Evidence Autophagy flux assays in vitro (LC3, p62) and in TTR V30M transgenic mouse gastrointestinal tissue with curcumin/TUDCA rescue

    PMID:25382970 PMID:27382986

    Open questions at the time
    • Whether autophagy impairment is cause or consequence of cytotoxicity not resolved
    • Molecular target through which TTR aggregates impair autophagy not identified
    • Replicated only in gastrointestinal tissue in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • The cellular receptor(s) or signaling pathways through which TTR monomers and small oligomers exert cytotoxicity, and the precise mechanism by which TTR aggregates impair autophagy, remain unresolved.
  • No receptor for oligomer-mediated toxicity identified
  • Structural basis of oligomer versus fibril differential toxicity not determined
  • In vivo contribution of neuronal TTR to neuroprotection versus liver-derived TTR not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 5 GO:0008289 lipid binding 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-1643685 Disease 5 R-HSA-382551 Transport of small molecules 4 R-HSA-9612973 Autophagy 2
Partners
HSF1RBP4
Complex memberships
TTR homo-tetramerTTR-RBP complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1974 Human plasma prealbumin (TTR) was determined to be a tetramer of identical subunits with a defined amino acid sequence, establishing the primary structure of the protein. Protein sequencing of cyanogen bromide and tryptic peptides The Journal of biological chemistry High 4607556
1978 X-ray crystallography at 1.8 Å resolution revealed that TTR (prealbumin) forms a β-strand-rich homo-tetramer with two thyroxine (T4) binding sites located at the dimer-dimer interface, defining the secondary, tertiary, and quaternary structure of the protein. X-ray crystallography, Fourier refinement at 1.8 Å Journal of molecular biology High 671542
1983 The amyloid fibril protein in familial amyloidotic polyneuropathy (Japanese type) was identified as a variant of TTR (prealbumin) in which valine at position 30 is replaced by methionine (Val30Met), establishing TTR as the precursor of familial amyloid in FAP. Peptide mapping, cyanogen bromide fragment comparison, sequence analysis of amyloid fibril protein versus normal prealbumin Biochemical and biophysical research communications High 6651852
1986 TTR mRNA is synthesized specifically by choroid plexus epithelial cells within the CNS, with no expression in cerebellum or cerebral cortex, and TTR protein is produced de novo by the choroid plexus for secretion into CSF, establishing choroid plexus as the site of CNS TTR production. Northern blot analysis of postmortem brain homogenates, in vitro translation assay of choroid plexus mRNA, immunocytochemistry, in situ hybridization in rat brain Neurology High 3714052
1987 The human TTR (prealbumin, PALB) gene was assigned to chromosome region 18q11.2-q12.1 by somatic cell hybrid analysis and in situ hybridization, establishing the chromosomal locus for the gene responsible for familial amyloidotic polyneuropathy. Somatic cell hybrid analysis with human genomic probe, in situ hybridization Human genetics High 3028932
1990 Amyloid fibrils in senile systemic amyloidosis (SSA) are derived from wild-type (normal primary structure) TTR, demonstrating that TTR amyloidogenesis does not require coding mutations and that factors other than primary sequence drive wild-type TTR misfolding. Protein sequencing of amyloid fibril protein isolated from SSA patients; comparison with normal TTR sequence Proceedings of the National Academy of Sciences of the United States of America High 2320592
1991 Site-directed mutagenesis of hepatocyte nuclear factor (HNF) binding sites in the TTR promoter revealed that the high-affinity HNF-3-S site (−106 to −94) is absolutely required for TTR promoter activity, and that synergistic cooperation between factors binding the promoter and distal enhancer is necessary for tissue-specific TTR expression in hepatoma cells. Site-directed mutagenesis of promoter elements, transfection into hepatoma cells, reporter gene assays Nucleic acids research High 1870969
1991 In vivo genomic footprinting of the mouse TTR promoter and enhancer in liver revealed liver-specific occupancy of certain DNA binding sites and identified additional protein-binding sites not previously detected in transfection studies, indicating that not all in vitro demonstrable sites are occupied during active transcription in vivo. In vivo genomic footprinting using biotinylated riboprobe purification and single primer extension with Taq polymerase in mouse liver Genes & development High 1989908
1993 The TTR Met119 variant (Thr119Met substitution) increases serum TTR concentration and T4 binding capacity, with increased T4 binding attributable to higher TTR levels rather than an increased association constant; elevated RBP (retinol-binding protein) in carriers also confirmed that TTR normally facilitates RBP retention in plasma. Serum dialysis with stepwise saturation, cyanogen bromide peptide mapping, DNA restriction fragment length polymorphism, family study The Journal of clinical endocrinology and metabolism Medium 8102146
1995 X-ray crystallography at 3.1 Å resolution of the TTR–retinol-binding protein (RBP) complex showed that one TTR tetramer binds two RBP molecules, both interacting with the same TTR dimer, with contacts near the retinol-binding site of RBP; the other two potential binding sites of the TTR tetramer were blocked by this arrangement. X-ray crystallography of the TTR–RBP co-crystal at 3.1 Å resolution Science High 7754382
1997 Retinol uptake from the RBP–TTR complex by primary rat hepatocytes (parenchymal and nonparenchymal cells) was approximately twofold greater than from RBP alone, uptake was inhibitable by excess free TTR, and nonparenchymal (stellate) cells converted most incorporated retinol to retinyl ester; these data indicate TTR acts as a positive regulator of RBP-bound retinol delivery, possibly via a membrane receptor. Primary cultured rat hepatocyte incubation with [3H]retinol-RBP or [3H]retinol-RBP-TTR, competitive inhibition assays, HPLC analysis of retinol metabolites Experimental cell research Medium 9260907
2000 The non-pathogenic TTR R104H variant, like TTR T119M, stabilizes the TTR tetramer against dissociation into monomers in compound heterozygotes carrying Val30Met, providing a molecular explanation for the protective effect of R104H on FAP progression; however, stability and T4 binding affinity are not obligatorily linked, as R104H shows increased stability but lower T4 binding affinity than T119M. Stability assays (resistance to dissociation into monomers), thyroxine binding studies comparing TTR variants Biochemical and biophysical research communications Medium 10772944
2000 Crystal structures of TTR complexed with several small-molecule inhibitors (flufenamic acid, diclofenac, flurbiprofen, resveratrol) at the T4-binding sites revealed the structural basis for stabilization of the native tetramer; structure-based drug design led to identification of ortho-trifluoromethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4,6-dicarboxylic acid as potent, selective TTR fibril formation inhibitors. X-ray crystallography of TTR–ligand complexes, in vitro fibril formation inhibition assays, structure-based drug design Nature structural biology High 10742177
2001 Incorporation of one or more T119M TTR subunits into a predominantly V30M TTR tetramer strongly stabilizes the mixed tetramer against dissociation, providing the molecular mechanism for intragenic trans-suppression of FAP amyloidosis; tetramer dissociation is required for amyloid formation, so stabilization by T119M subunits prevents V30M-driven aggregation. Biophysical analysis of mixed V30M/T119M TTR tetramers; dissociation assays under denaturing conditions; analytical ultracentrifugation Science High 11577236
2003 Kinetic stabilization of the native TTR tetramer by small molecules raises the kinetic barrier to misfolding and prevents amyloidogenesis; the protective T119M trans-suppressor mutation likewise acts through kinetic stabilization rather than thermodynamic stabilization, establishing kinetic stabilization of the native state as a valid therapeutic strategy. In vitro TTR amyloidogenesis inhibition assays, rate constant measurements for tetramer dissociation, comparison of small molecules and the T119M variant Science High 12560553
2004 TTR monomers and small non-native oligomers (≤6 subunits, <100 kDa) are the major cytotoxic species to neural lineage cells; TTR amyloid fibrils and large soluble aggregates (>100 kDa) are not toxic; small molecules that stabilize the native tetramer prevent this toxicity, supporting a model in which tetramer dissociation → misfolded monomer → small aggregates is the cytotoxic pathway. Cell viability assays with size-fractionated TTR quaternary structures (size-exclusion chromatography, SDS-PAGE), small molecule rescue experiments in cell culture Proceedings of the National Academy of Sciences of the United States of America High 14981241
2011 Natural polyphenols curcumin, NDGA, and EGCG bind TTR and modulate fibrillogenesis by distinct mechanisms: curcumin and NDGA stabilize the TTR tetramer, while curcumin generates small off-pathway oligomers, EGCG maintains protein in a non-aggregated soluble form, and both curcumin and EGCG can disaggregate pre-formed TTR amyloid fibrils. In vitro TTR fibril formation assays, binding studies, transmission electron microscopy, disaggregation assays FEBS letters Medium 21740906
2012 Nearly 200 X-ray crystal structures of TTR have revealed that TTR forms two T4-binding sites at the dimer-dimer interface and holo-RBP binding sites on both faces of the tetramer; structural studies define the mechanistic role of specific structural elements in TTR misfolding and amyloid formation, and guide rational inhibitor design targeting tetramer stabilization. Review and synthesis of X-ray crystallographic data from ~200 TTR structures and ligand complexes Current medicinal chemistry High 22471981
2014 TTR expression in neuronal cells (SH-SY5Y, primary hippocampal neurons, and APP23 mouse hippocampus) is upregulated by heat shock factor 1 (HSF1), which directly occupies heat shock elements in the TTR promoter in neurons but not in liver, HepG2 hepatoma cells, or cardiomyocytes; this neuron-specific transcriptional regulation by HSF1 is triggered by heat shock or HSF1 stimulator celastrol and is blocked by HSF1 antisense. Chromatin immunoprecipitation (ChIP) assays in vivo and in cell culture, HSF1 overexpression/knockdown, celastrol treatment, Northern/Western blot analysis The Journal of neuroscience High 24849358
2014 TTR Y114C mutation leads to increased monomeric TTR and impaired autophagy (as shown by autophagic marker accumulation); curcumin treatment significantly decreases monomeric TTR by recovering autophagic flux in a cell model of FAP, implicating autophagy impairment in TTR FAP pathogenesis. Cell model with TTR Y114C transfection, autophagy flux assays (LC3, p62 markers), curcumin treatment, Western blot Drug design, development and therapy Medium 25382970
2016 TTR V30M aggregates cause partial impairment of autophagic machinery (p62 accumulation) in cell culture while early autophagic steps remain intact; in TTR V30M transgenic mice, tauroursodeoxycholic acid (TUDCA) and curcumin reverse p62 accumulation in the gastrointestinal tract, demonstrating that both compounds modulate autophagy in addition to mitigating apoptosis. Cell culture autophagy flux assays (p62, LC3, autophagosome quantification), in vivo TTR V30M transgenic mouse model, TUDCA and curcumin treatment, immunohistochemistry Clinical science Medium 27382986
2018 TTR stabilizers act at the TTR dimer-dimer interface to prevent dissociation of TTR tetramers into amyloidogenic monomers, representing the mechanistic basis for their therapeutic action in TTR cardiac amyloidosis. Retrospective clinical study with mechanistic framing; mechanism cited from prior biochemical studies Circulation. Heart failure Low 29615436
2019 Hydrophilic extract of Centella asiatica (CAB) bound to human TTR, stabilized the native homo-tetramer against acid/urea-mediated denaturation, and prevented TTR fibrillation in vitro; the binding was demonstrated by NBT redox-cycling and ANS displacement assays, with phenolics and terpenoids identified as likely active components. Acid/urea denaturation stability assays, transmission electron microscopy of fibrils, NBT redox-cycling assay, ANS displacement assay, HPLC-QTOF-MS for chemical profiling Biomolecules Medium 30934952
2024 TNF-α stimulation of rheumatoid arthritis synoviocytes upregulates TTR and RAGE protein expression via NF-κB pathway activation; apigenin reduces p65, TTR, and RAGE levels both in vitro and in vivo in an RA model, indicating that TTR expression in synoviocytes is NF-κB-dependent and modulated by anti-inflammatory compounds. TNF-α stimulation of human RA synovial fibroblasts, apigenin treatment, in-silico docking, Western blot (p65, TTR, RAGE), in vivo RA mouse model Cytokine Medium 38626647

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1978 Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 A. Journal of molecular biology 729 671542
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1990 Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proceedings of the National Academy of Sciences of the United States of America 584 2320592
2012 Transthyretin (TTR) cardiac amyloidosis. Circulation 527 22949539
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2016 Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). Journal of the American College of Cardiology 429 27386769
2003 Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science (New York, N.Y.) 428 12560553
2013 Atomic structure and hierarchical assembly of a cross-β amyloid fibril. Proceedings of the National Academy of Sciences of the United States of America 416 23513222
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
1995 Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science (New York, N.Y.) 346 7754382
2000 Rational design of potent human transthyretin amyloid disease inhibitors. Nature structural biology 324 10742177
1986 Transthyretin: a choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award. Neurology 322 3714052
1983 Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type). Biochemical and biophysical research communications 314 6651852
2004 Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proceedings of the National Academy of Sciences of the United States of America 311 14981241
1994 Transthyretin (prealbumin) in health and disease: nutritional implications. Annual review of nutrition 300 7946531
1974 The amino acid sequence of human plasma prealbumin. The Journal of biological chemistry 291 4607556
2006 Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. The International journal of developmental biology 282 16892178
2014 Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation 266 24563469
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2001 Trans-suppression of misfolding in an amyloid disease. Science (New York, N.Y.) 253 11577236
2004 An investigation into the human serum "interactome". Electrophoresis 247 15174051
2004 Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy. Neurology 190 15249622
2007 Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP). Neurology 179 17698792
2016 Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Current opinion in neurology 172 26734951
2019 Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 149 30793974
2015 Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 142 26123279
2011 Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation. FEBS letters 131 21740906
2007 Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin). The Journal of neuroscience : the official journal of the Society for Neuroscience 115 17596449
2010 Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor. Nature cell biology 101 20526330
1991 Site-directed mutagenesis of hepatocyte nuclear factor (HNF) binding sites in the mouse transthyretin (TTR) promoter reveal synergistic interactions with its enhancer region. Nucleic acids research 98 1870969
1996 Familial meningocerebrovascular amyloidosis, Hungarian type, with mutant transthyretin (TTR Asp18Gly). Neurology 83 8960746
2018 TTR (Transthyretin) Stabilizers Are Associated With Improved Survival in Patients With TTR Cardiac Amyloidosis. Circulation. Heart failure 79 29615436
1999 Regulated nuclear localisation of the yeast transcription factor Ace2p controls expression of chitinase (CTS1) in Saccharomyces cerevisiae. Molecular & general genetics : MGG 79 10517323
2005 Candida albicans CHT3 encodes the functional homolog of the Cts1 chitinase of Saccharomyces cerevisiae. Fungal genetics and biology : FG & B 75 16214381
2015 Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP): A Single-Center Experience in Sicily, an Italian Endemic Area. Journal of neuromuscular diseases 72 27858761
2019 LncRNA-CTS promotes metastasis and epithelial-to-mesenchymal transition through regulating miR-505/ZEB2 axis in cervical cancer. Cancer letters 71 31499118
2017 Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 70 28906150
2021 Prevalence and Outcomes of p.Val142Ile TTR Amyloidosis Cardiomyopathy: A Systematic Review. Circulation. Genomic and precision medicine 67 34461737
2016 Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy. Open heart 66 26870387
2012 Nearly 200 X-ray crystal structures of transthyretin: what do they tell us about this protein and the design of drugs for TTR amyloidoses? Current medicinal chemistry 65 22471981
2011 Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients. Journal of the peripheral nervous system : JPNS 65 21692911
2000 Review: TTR amyloidosis-structural features leading to protein aggregation and their implications on therapeutic strategies. Journal of structural biology 64 10940233
1998 Ace2p, a regulator of CTS1 (chitinase) expression, affects pseudohyphal production in Saccharomyces cerevisiae. Current genetics 61 9745020
2014 Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. Journal of the neurological sciences 60 25012480
2012 Applying unconventional secretion of the endochitinase Cts1 to export heterologous proteins in Ustilago maydis. Journal of biotechnology 58 22446315
1991 Rapid in vivo footprinting technique identifies proteins bound to the TTR gene in the mouse liver. Genes & development 58 1989908
2005 Rett syndrome in females with CTS hot spot deletions: a disorder profile. American journal of medical genetics. Part A 56 15578576
2000 Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119M. Biochemical and biophysical research communications 53 10772944
2021 Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy. Neurology and therapy 50 33638113
2008 Physiological involvement in pH signaling of Vps24-mediated recruitment of Aspergillus PalB cysteine protease to ESCRT-III. The Journal of biological chemistry 50 19056728
2019 Clinical Presentation, Diagnosis and Treatment of TTR Amyloidosis. Journal of neuromuscular diseases 49 30829617
2020 The Positive Side of the Alzheimer's Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1. Molecules (Basel, Switzerland) 48 32456156
2011 The RNA-binding protein Rrm4 is essential for efficient secretion of endochitinase Cts1. Molecular & cellular proteomics : MCP 47 21808052
2012 Promoter swapping unveils the role of the Citrobacter rodentium CTS1 type VI secretion system in interbacterial competition. Applied and environmental microbiology 46 23064344
2016 TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies. Expert opinion on pharmacotherapy 45 26800456
2014 The systemic amyloid precursor transthyretin (TTR) behaves as a neuronal stress protein regulated by HSF1 in SH-SY5Y human neuroblastoma cells and APP23 Alzheimer's disease model mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 45 24849358
1987 Assignment of the prealbumin (PALB) gene (familial amyloidotic polyneuropathy) to human chromosome region 18q11.2-q12.1. Human genetics 45 3028932
2012 TTR-related amyloid neuropathy: clinical, electrophysiological and pathological findings in 15 unrelated patients. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 44 22592564
1995 Isolation and characterization of two chitinase-encoding genes (cts1, cts2) from the fungus Coccidioides immitis. Gene 42 8566773
2009 Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian families. European journal of neurology 39 19364362
2003 Phospholipid-binding protein Cts1 controls septation and functions coordinately with calcineurin in Cryptococcus neoformans. Eukaryotic cell 39 14555485
2018 Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. Human mutation 38 30328212
2016 The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Molecular genetics & genomic medicine 37 27652282
1992 Two transthyretin variants (TTR Ala-49 and TTR Gln-89) in two Sicilian kindreds with hereditary amyloidosis. Human mutation 35 1301926
1993 Thyroxine binding in a TTR Met 119 kindred. The Journal of clinical endocrinology and metabolism 34 8102146
2021 In vitro human cell-based TTR-TRβ CALUX assay indicates thyroid hormone transport disruption of short-chain, medium-chain, and long-chain chlorinated paraffins. Archives of toxicology 33 33555371
2013 Neurophysiological markers of small fibre neuropathy in TTR-FAP mutation carriers. Journal of neurology 33 23306657
2009 Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met. Journal of the neurological sciences 33 19493541
2020 Heavy metal ions' poisoning behavior-inspired etched UiO-66/CTS aerogel for Pb(II) and Cd(II) removal from aqueous and apple juice. Journal of hazardous materials 32 32623307
2009 Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid. The American journal of surgical pathology 30 18830126
2022 In silico analysis decodes transthyretin (TTR) binding and thyroid disrupting effects of per- and polyfluoroalkyl substances (PFAS). Archives of toxicology 29 36566436
2009 Antibodies to protein tyrosine phosphatase receptor type O (PTPro) increase glomerular albumin permeability (P(alb)). American journal of physiology. Renal physiology 29 19403647
2018 Evaluation of HE4 and TTR for diagnosis of ovarian cancer: Comparison with CA-125. Journal of gynecology obstetrics and human reproduction 28 29609043
2022 Neuropathology of central nervous system involvement in TTR amyloidosis. Acta neuropathologica 27 36198883
2013 Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation. Eye (London, England) 27 24113303
2011 Transcription of Aspergillus nidulans pacC is modulated by alternative RNA splicing of palB. FEBS letters 27 21985967
1998 CTS1: a p53-derived chimeric tumor suppressor gene with enhanced in vitro apoptotic properties. The Journal of clinical investigation 27 9421473
2023 Lessons from the first-in-human in vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 trial in patients with transthyretin amyloidosis with cardiomyopathy. Global cardiology science & practice 26 37928601
2017 Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. European journal of human genetics : EJHG 25 28635949
2014 Regulating drug release from pH- and temperature-responsive electrospun CTS-g-PNIPAAm/poly(ethylene oxide) hydrogel nanofibers. Biomedical materials (Bristol, England) 25 25135109
2015 Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia. Acta neuropathologica communications 24 26156087
2013 Preparation and drug release mechanism of CTS-TAX-NP-MSCs drug delivery system. International journal of pharmaceutics 24 23933442
2009 Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse. Hepatology research : the official journal of the Japan Society of Hepatology 24 19624765
2018 Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 23 30169969
2015 Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis. Molecules (Basel, Switzerland) 23 26437390
2009 Identification and characterization of the chromium (VI) responding protein from a newly isolated Ochrobactrum anthropi CTS-325. Journal of environmental sciences (China) 23 20131597
2019 Structural Stabilization of Human Transthyretin by Centella asiatica (L.) Urban Extract: Implications for TTR Amyloidosis. Biomolecules 22 30934952
1996 A novel human leukaemic cell line, CTS, has a t(6;11) chromosomal translocation and characteristics of pluripotent stem cells. British journal of haematology 22 8904886
2022 A natural history analysis of asymptomatic TTR gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS). Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 20 35730447
2019 Specific growth rates calculated from CTs in patients with head and neck squamous cell carcinoma: a retrospective study performed in Austria. BMJ open 20 30782931
2019 Clinicopathological correlations of sural nerve biopsies in TTR Val30Met familial amyloid polyneuropathy. Brain communications 20 32954271
2016 Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey. Neuromuscular disorders : NMD 20 27238058
2003 The Saccharomyces cerevisiae chitinase, encoded by the CTS1-2 gene, confers antifungal activity against Botrytis cinerea to transgenic tobacco. Transgenic research 20 12885170
2019 Founder effect of the Glu89Gln TTR mutation in the Bulgarian population. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 19 31353960
1997 Interactions of transthyretin (TTR) and retinol-binding protein (RBP) in the uptake of retinol by primary rat hepatocytes. Experimental cell research 19 9260907
2019 Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD. Scientific reports 17 31541162
2011 Residual HIV-1 DNA Flap-independent nuclear import of cPPT/CTS double mutant viruses does not support spreading infection. Retrovirology 17 22074589
2014 Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 16 25510352
2011 The C2 domain protein Cts1 functions in the calcineurin signaling circuit during high-temperature stress responses in Cryptococcus neoformans. Eukaryotic cell 16 22002655
2000 Pathology of familial amyloidotic polyneuropathy with TTR met 30 in Kumamoto, Japan. Neuropathology : official journal of the Japanese Society of Neuropathology 16 11037187
2020 DISCOVERY: prevalence of transthyretin (TTR) mutations in a US-centric patient population suspected of having cardiac amyloidosis. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 15 32456532
2012 Methods to evaluate the inhibition of TTR fibrillogenesis induced by small ligands. Current medicinal chemistry 15 22471983
2012 Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment. Genes & development 15 22713871
2024 Targeting TNF-α-induced expression of TTR and RAGE in rheumatoid arthritis: Apigenin's mediated therapeutic approach. Cytokine 14 38626647
2021 Chitosan (CTS) Alleviates Heat-Induced Leaf Senescence in Creeping Bentgrass by Regulating Chlorophyll Metabolism, Antioxidant Defense, and the Heat Shock Pathway. Molecules (Basel, Switzerland) 14 34500767
2018 Self-assembling peptide and nHA/CTS composite scaffolds promote bone regeneration through increasing seed cell adhesion. Materials science & engineering. C, Materials for biological applications 14 30274077
2014 Isolated heart transplantation for familial transthyretin (TTR) V122I cardiac amyloidosis. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 14 24818650
2011 Technetium pyrophosphate myocardial uptake and peripheral neuropathy in a rare variant of familial transthyretin (TTR) amyloidosis (Ser23Asn): a case report and literature review. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 14 22149423
2020 A Novel Factor Essential for Unconventional Secretion of Chitinase Cts1. Frontiers in microbiology 13 32733418
2019 Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 13 31554435
2019 Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses. Human genetics 13 31659433
2007 Oculoleptomeningeal amyloidosis in a patient with a TTR Val30Gly mutation in the transthyretin gene. Ophthalmology 13 17980738
2021 Metformin-loaded β-TCP/CTS/SBA-15 composite scaffolds promote alveolar bone regeneration in a rat model of periodontitis. Journal of materials science. Materials in medicine 12 34862928
2016 Impairment of autophagy by TTR V30M aggregates: in vivo reversal by TUDCA and curcumin. Clinical science (London, England : 1979) 12 27382986
2014 Curcumin could reduce the monomer of TTR with Tyr114Cys mutation via autophagy in cell model of familial amyloid polyneuropathy. Drug design, development and therapy 12 25382970
2012 [Identification of a TTR gene mutation in a family with hereditary vitreous amyloidosis]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 12 22311483
2006 PCTAIRE3: a putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells. Cancer gene therapy 12 16276348
2000 Cancer gene therapy mediated by CTS1, a p53 derivative: advantage over wild-type p53 in growth inhibition of human tumors overexpressing MDM2. Cancer gene therapy 12 10830726
1999 Aspergillus oryzae palBory encodes a calpain-like protease: homology to Emericella nidulans PalB and conservation of functional regions. Journal of bioscience and bioengineering 12 16232641
2016 The transcription factor Ace2 and its paralog Swi5 regulate ethanol production during static fermentation through their targets Cts1 and Rps4a in Saccharomyces cerevisiae. FEMS yeast research 11 26975390
2012 Familial amyloidosis with polyneuropathy associated with TTR Ser50Arg mutation. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 11 22928869