Disease relevance of Ttr

• Decreased expression of hepatocyte nuclear factor 3 alpha during the acute-phase response influences transthyretin gene transcription [1].
• We have previously characterized a strong-affinity HNF-3S site in the transthyretin (TTR) promoter region which is essential for expression in human hepatoma (HepG2) cells [1].
• In an attempt to establish an animal model of TTR Met-30-associated homozygous familial amyloidotic polyneuropathy and to study the structural and functional properties of human TTR Met 30, we generated a mouse line carrying a null mutation at the endogenous ttr locus (ttr-/-) and the human mutant ttr gene (6.0-hMet 30) as a transgene [2].
• Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: a possible model for senile systemic amyloidosis [3].
• The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis [3].

Psychiatry related information on Ttr

• Transthyretin-null mice responded as the wild-type both to changes induced by stressful events, namely in body weight, food intake and thyroid hormone tissue content, and in the mRNA levels of genes whose expression is altered in such conditions [4].
• An association study between the transthyretin (TTR) gene and mental retardation [5].
• Differential post-translational modifications of transthyretin in Alzheimer's disease: A study of the cerebral spinal fluid [6].

High impact information on Ttr

• Only the most highly destabilized TTR variants are subjected to ER-associated degradation (ERAD) and then only in certain tissues, providing insight into tissue selective amyloidosis [7].
• Genes for immunoglobulin heavy chain and serum prealbumin protein are linked in mouse [8].
• One factor recognizes the liver-specific enhancers in alpha 1-antitrypsin and transthyretin genes [9].
• These loci are located in a tightly linked cluster between the immunoglobulin heavy chain constant region gene cluster, Igh-C, and the serum prealbumin locus Pre-1, in this manner: centromere--Igh-C--(Tthy, Tind)-Tsu-Tpre--Pre-1 [10].
• Distinct positive and negative elements control the limited hepatocyte and choroid plexus expression of transthyretin in transgenic mice [11].

Chemical compound and disease context of Ttr

• Induction of the expression of retinol-binding protein and transthyretin in F9 embryonal carcinoma cells differentiated to embryoid bodies [12].
• The vector consists of part of ttr carrying a subtle mutation in its second exon, and a cassette of the neomycin-resistance (neo)- and herpes simplex virus thymidine kinase (HSV-tk)-encoding genes flanked with a 3-kb duplication of mostly the second intron of ttr [13].

Biological context of Ttr

• In conclusion, our model proposes that in response to reduction in hepatocyte glycogen storage, the TTR-Foxa2 TG mice survive by maintaining sufficient serum levels of glucose through gluconeogenesis using deaminated amino acids with dicarboxylate products of peroxisomal lipid beta-oxidation shuttled through the tricarboxylic acid cycle [14].
• Analysis of the TTR-1 site demonstrates that the putative AP-1 site in the TTR enhancer binds a ubiquitously expressed factor that is distinct from the AP-1 family of proteins [15].
• Using backcross analysis, the Gata6 gene was localized to mouse chromosome 18, linked to the gene encoding transthyretin [16].
• The TTR enhancer was shown to bind members of the CCAAT/enhancer binding protein (C/EBP) family at two distinct sites (TTR-2 and TTR-3), and an oligonucleotide containing the activation protein one (AP-1) binding sequence competed for recognition to a third enhancer site (TTR-1) [15].
• A minigene, in which the promoter region of the mouse myelin basic protein (MBP) gene was ligated to the human mutant TTR cDNA, was used for microinjection [17].

Anatomical context of Ttr

• In order to examine the regulatory function of HNF-3beta, we created transgenic mice in which the -3-kb transthyretin promoter functions to increase hepatocyte expression of the rat HNF-3beta protein [18].
• At 6-7.5 days of gestation, high levels of vHNF1 mRNA are present in the visceral extraembryonic endoderm, which co-localize with transcripts of the transthyretin gene [19].
• Transthyretin (TTR) is the principal carrier of thyroid hormones in rodent plasma and the major protein synthesized by the choroid plexus [20].
• Levels of retinol and retinyl esters in testis, kidney, spleen, and eye cups from TTR- mice were normal [21].
• We found that the levels of noradrenaline were significantly increased in the limbic forebrain of TTR-null mice [22].

Associations of Ttr with chemical compounds

• Furthermore, we show that elevated HNF-3beta levels stimulate expression of endogenous TTR and Shh without retinoic acid stimulation [23].
• Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone [24].
• Transthyretin (TTR) is thought to play a major role in vitamin A metabolism and thyroid hormone transport in mammals [24].
• In pooled plasma from the TTR- mice retinol levels averaged 6% of those of wild type animals [21].
• TTR is a tetramer composed of four identical subunits that binds thyroxine (T4) and plasma retinol-binding protein [2].

Physical interactions of Ttr

• Identification of a transthyretin enhancer site that selectively binds the hepatocyte nuclear factor-3 beta isoform [15].
• Transthyretin plays a role in hormone transport in the brain and possibly a neuroprotective role by amyloid-beta sequestration [25].

Regulatory relationships of Ttr

• The strain difference, peroxisome proliferator specificity and role of PPAR alpha in peroxisome proliferator-induced transcriptional repression of nonperoxisomal transthyretin and alpha2u-globulin genes were examined [26].

Other interactions of Ttr

• We demonstrate that adenovirus-mediated increase of HNF-3alpha levels in F9 cells is sufficient to induce activation of endogenous HNF-3beta levels followed by increased TTR and Shh expression [23].
• During breeding of the TTR-HNF-3beta transgenic mice we noticed that they displayed severe ataxia [27].
• In the current study, we identify an activating protein 1 (AP-1) site which partially overlaps the HNF-3S sequence in the TTR promoter [1].
• In this work, we identify a liver-enriched transcription factor, HNF-6, which recognizes the -138 to -126 region of the HNF-3(beta) promoter and binds the original HNF-3 site of the transthyretin promoter (-94 to -106) [28].
• Mice lacking TTR generated by targeted disruption (Episkopou, V., Maeda, S., Nishiguchi, S., Shimada, K., Gaitanaris, G. A., Gottesman, M. E., and Robertson, E. J. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2375-2379) had a 50% decrease in total thyroxine (T4) plasma levels but had normal free hormone levels as compared to wild-type mice [20].

Analytical, diagnostic and therapeutic context of Ttr

• Chromosomal localization of the mouse prealbumin gene (Ttr) by in situ hybridization [29].
• To investigate the physiological role of the TTR protein in development of the embryo and in the adult, we used gene targeting techniques to generate a null mutation at the mouse ttr locus [24].
• Partial hepatectomy produced minimal fluctuation in HNF-3 and TTR expression, suggesting that HNF-3 expression is not influenced by proliferative signals induced during liver regeneration [1].
• Site-directed mutagenesis of the HNF-6 sites in the HNF-3(beta) and transthyretin promoters diminishes reporter gene expression, suggesting that HNF-6 activates transcription of these promoters [28].
• Immunocytochemistry was performed to localize short and mid-long wavelength cone opsins as well as morphological examination of the entire retina in wild-type and TTR null mice [30].

References