Disease relevance of TSHR

• We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments [1].
• The importance of thyrotropin receptor (TSHR) agonist antibodies in the manifestations of Graves' disease (GD) is recognized [2].
• This pathway may be constitutively activated by mutations of the TSH receptor (TSHR) and Gsalpha in autonomous thyroid adenomas (ATAs) [3].
• Therefore, we screened for mutations in the TSHR gene in patients with congenital hypothyroidism and hypoplasia of the gland [4].
• To identify such reactions, we analyzed the T-cell proliferative responses of peripheral blood lymphocytes (PBMC) to human recombinant TSHR extracellular domain (hrecTSHR-ECD amino acids 19-417) expressed in Escherichia coli and to Tg [5].

Psychiatry related information on TSHR

• Polymorphisms in the TSHR (thyrotropin receptor) gene on chromosome 14q31 are not associated with mental retardation in the iodine-deficient areas of China [6].
• Thyroid stimulating hormone-receptor overexpression in brain of patients with Down syndrome and Alzheimer's disease [7].

High impact information on TSHR

• It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs) [8].
• The thyrotropin receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase [1].
• Evidence that the TSH receptor acts as a mitogenic antigen in Graves' disease [9].
• In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter [10].
• Graves' hyperthyroidism can be induced in mice or hamsters by novel approaches, namely injecting cells expressing the TSH receptor (TSHR) or vaccination with TSHR-DNA in plasmid or adenoviral vectors [11].

Chemical compound and disease context of TSHR

• To investigate the influence of thyroid hormone status on adipose TSHR expression, we induced hyper- and hypothyroidism in BALBc mice by administering tri-iodothyronine and propylthiouracil respectively [12].
• RESULTS: A heterozygous germline mutation of the TSHR gene resulting in the substitution of serine (AGC) by asparagine (AAC) at codon 505 (S505N) was found, which co-segregated with thyrotoxicosis in the family [13].
• An activating mutation of the TSH receptor gene in both the primary tumor and the lymph node metastasis was found, due to a base substitution at codon 633 (normal guanine at position 1896 replaced by cytosine CAC for GAC causing aspartic acid substitution by histidine) [14].
• Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the 10th exons (bp 1012-1704) of the TSH receptor gene in Graves' disease [15].
• Thyroid-stimulating hormone-receptor antibody measurements at 36 weeks' gestation are predictive of transient neonatal hyperthyroidism, and should be checked even in previously treated patients receiving thyroxine [16].

Biological context of TSHR

• Thus, this new potent method of antigen presentation, using autoantigen-transfected EBVL, has permitted the first unequivocal identification of TSHR T cells in GD thyroid, with distinct Th0/Th2 characteristics, unlike previously cloned TPO-responsive cells which have Th1 characteristics [2].
• TSH and cAMP increased the tyrosine phosphorylation of TSHR and the association between TSHR and the p85alpha regulatory subunit of PI3K [17].
• Binding and competition analyses are consistent with the presence of two binding sites on the TSHR transfected baby hamster kidney cells, one that can interact with either TSH or CGH, and another that binds CGH alone [18].
• Thus, transfected into rat FRTL-5 cells, the activity of reporter plasmids, containing rat TSHR promoter ligated to a chloramphenicol acetyltransferase gene, was significantly suppressed in the presence of rat IFN gamma [19].
• Germline mutations of TSHR may be associated with serum TSH values fluctuating above the upper limit of the normal range, also in the heterozygous state [20].

Anatomical context of TSHR

• There are, however, no convincing reports of TSHR-specific T cells [2].
• Inhibition of acquisition of N-linked oligosaccharides by tunicamycin treatment in CHO cells stably expressing TSHR produced nonglycosylated TSHR, which was totally nonfunctional [21].
• These data demonstrate that acquisition and processing of N-linked oligosaccharides of TSHR appear to be essential for correct folding in the endoplasmic reticulum and for cell surface targeting in the Golgi apparatus [21].
• To investigate whether this reflects an inherent difference in their oncogenic potency, we compared the effects of retrovirally-transduced mutant (A623I) TSHR or (Q227L) Galphas (GSP), using the rat thyroid cell line FRTL5 and primary human thyrocytes [22].
• Functional expression of the mutant TSHR-R528H in COS-7 cells, however, did not result in constitutive activity of the TSHR [23].

Associations of TSHR with chemical compounds

• In contrast, all of the TSHRs synthesized in mutant CHO-Lec1, 2, and 8 cells (mannose-rich, sialic acid-deficient, and galactose-deficient oligosaccharides, respectively) bound TSH and produced cAMP in response to TSH with an affinity and an EC50 similar to those in TSHR expressed in parental CHO cells (CHO-TSHR; sialylated oligosaccharides) [21].
• The amino-terminal ectodomain of thyrotropin (TSH) receptor (TSHR) is heavily glycosylated with asparagine-linked (N-linked) oligosaccharides [21].
• In this study, we sequenced the entire TSHR gene in a series of 10 unrelated patients with slight (6.6-14.9 mU/liter) to moderate (24-46 mU/liter) elevations of serum TSH, associated with definitely normal free thyroid hormone concentrations [20].
• In the boy and his mother, an identical heterozygous TSHR mutation was identified, exchanging leucine for phenylalanine at residue 629 of the TSHR (TTG-->TTT) [24].
• OBJECTIVES: To find whether germline and somatic gain-of-function mutations of the thyrotropin receptor (TSHR) differ in location and/or mutational mechanisms, as well as to explore the degree to which these mutations are specific to TSHR compared with pituitary glycoprotein hormone receptors [25].

Physical interactions of TSHR

• Chemical modification of the parent compound combined with prior mutagenesis of TSHR provided compelling experimental evidence in support of computational models of 3 binding to TSHR and LHCGR within their transmembrane cores [26].
• The gene for the FSH receptor is large (greater than 85 kb) and complex (10 introns) and is structurally similar to the genes for the LH and TSH receptor [27].
• In conclusion, IFN gamma interacts via an intermediate pathway of TSH signal transduction and attenuates TSH receptor synthesis in normal and Graves' thyroid cells [28].

Regulatory relationships of TSHR

• From these results, we conclude that IFN gamma suppresses TSHR promoter activity, in part, by reducing TTF-1 binding to its recognition site [19].
• Cross-talk appears to regulate G-protein interactions or activities induced by TSH as well as TSHR gene expression [29].
• Because thyroid cancer cells express functional TSH receptors (TSHR), TSHR-mRNA in peripheral blood might serve as a tissue-/cancer-specific marker [30].
• Relationship between CTLA-4 and CD28 molecule expression on T lymphocytes and stimulating and blocking autoantibodies to the TSH-receptor in children with Graves' disease [31].
• Thyroid-stimulating hormone receptor expressing cells also expressed the sodium iodide symporter and thyroglobulin genes [32].

Other interactions of TSHR

• These findings suggest that the TSHR is able to signal through JAK/STAT3 pathways [33].
• The reactivity to Tg was less than that to TSHR-ECD in both groups [5].
• Linkage of RTSH to TSHR and PAX8 was excluded in all five families [34].
• By RT-PCR, increments of PDE4D and 4C messenger ribonucleic acids were found in the ATAs with mutant TSHR or Gsalpha, whereas messenger ribonucleic acids encoding other cAMP-specific PDEs were not significantly increased [3].
• Whereas the affinity and specificity of hCG for LHR are extraordinarily high, the hormone is capable of binding to and activating both TSHR and FSHR under these conditions that mimic high ligand concentrations [35].

Analytical, diagnostic and therapeutic context of TSHR

• Activating mutations are, however, more common in the thyrotropin receptor (TSHR) than in its downstream transducer, Galphas [22].
• There was 100% concordance between TSHR and Tg mRNA RT-PCR results [36].
• Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically [37].
• Remarkably, only 4 of 21 TBI-positive sera (including BBI) unequivocally recognized the TSHR on flow cytometry [38].
• In one girl detected in neonatal screening with the confirmed diagnosis of permanent congenital hypothyroidism with reduced thyroid volume, two novel mutations in the TSHR gene were identified [4].

References