Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factors are frequently involved in the regulation of mitosis and differentiation of several cell types and insulin-like growth factor-1 (IGF-1) is actively involved in the thyroid stimulating hormone-mediated proliferation of thyrocytes. In view of the pivotal role of IGF-1 in thyrocyte proliferation and of the still unsettled role of this growth factor in the pathogenesis of hyperplastic thyroid lesions, we investigated the expression of IGF-1 and of its corresponding receptor, by means of immunohistochemistry, in the surgical specimens obtained from six patients with Graves' disease. Moreover, IGF-1 mRNA expression was analysed in one such case by means of Northern hybridisation. All samples showed consistent intracytoplasmic immunoreactivity for both IGF-1 and IGF-1 receptor; the vast majority of hyperplastic thyrocytes were strongly decorated by the two antibodies used in this study whereas stromal cells displayed IGF-1 immunoreactivity only. IGF-1 mRNA was markedly overexpressed in Graves' disease in comparison with normal thyroid tissues. The results of this study suggest that IGF-1 and IGF-1 receptor may be actively involved in the pathogenesis of Graves' disease; furthermore, IGF-1 and IGF-1 receptor apparently act by different mechanisms (paracrine vs. autocrine) as suggested by their differential expression in epithelial and stromal cells.
Int J Mol Med 1998 Oct
PMID:Insulin-like growth factor-1 and insulin-like growth factor receptor in thyroid tissues of patients with Graves' disease. 985 39

The immunological mechanisms leading to Graves' disease are not yet fully understood. The athymic nude mouse has immunological properties which allow in vivo studies concerning autoimmune thyroid diseases with special regard to the interaction of TSH, TSH receptor antibodies, cytokines, antithyroid drugs, TSH receptor antagonists and human lymphocytes. In our own studies thyroid tissues of patients with Graves' disease, toxic adenomas and non-toxic nodular goiter were xenotransplanted to athymic nude mice. Histology, morphology and function of the transplants were examined 2 days to 2 weeks after injection of bovine TSH, interferon-gamma, Graves' sera with or without addition of a TSH-receptor antagonist and lymphocytes of patients with Graves' disease. Thyroid transplants can be stimulated by TSH, interferon-gamma, Graves' sera and immunoglobulin G. Additional treatment with asialoagalacto-hCG inhibits stimulation of the immunoglobulin. Furthermore, preliminary results show, that engrafted peripheral and especially intrathyroidal lymphocytes from patients with Graves' disease specifically migrate into human thyroid transplants ("homing") and are able to induce functional and histological changes in these tissues. In summary, the xenotransplantation model is well suited for studies concerning pathogenesis, diagnosis and therapy of autoimmune thyroid diseases.
J Mol Med (Berl) 1999 Jan
PMID:Graves' disease: xenotransplantation model (athymic nude mice). 993 Sep 60

For investigation of the mechanism and pathogenesis of Graves' disease, availability of a large amount of functional human thyrotropin receptor (TSHR) capable of recognition by Graves' autoantibodies is essential. Many attempts have been made to produce the extracellular domain of TSH receptor (TSHRE) in a baculovirus expression system. However, the receptor is expressed as an insoluble form and the refolded protein is often not recognized by the autoantibodies. In this study, we found that the TSHRE expressed with its own signal peptide (VL3-RE) in insect cells is retained inside of the cells and found in both soluble and insoluble fractions in equal proportion. The signal peptide is not removed. The receptor in the soluble fraction is not recognized by either TSH or Graves' autoantibodies. The TSHRE with an insect-specific mellitin signal peptide (Mel-RE) is also retained inside of the cell and found in both the soluble and insoluble fractions in equal proportion. However, the signal peptide is removed and the receptor is recognized by the Graves' autoantibodies but not by TSH. Also, the amount of Mel-RE expressed was 5-10-fold higher than VL3-RE. The two receptor preparations apparently have the same degree of glycosylation as evidenced by the same increased mass (approximately 15 kDa) due to glycosylation. However, the two receptors have different affinity for an anion-exchange resin and different pI. Deglycosylated receptors have the same pI. This suggests that the composition of sugars may be different. Taken together, the results suggest that the two receptors are modified and folded differently by different pathways due to the presence of different signal peptides. Use of an insect-specific signal peptide is recommended for expression of TSHR that is recognized by Graves' autoantibodies in a baculovirus system.
Mol Cell Endocrinol 1999 Jan 25
PMID:Different bioactivities of human thyrotropin receptors with different signal peptides. 1019

Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.
Hum Mol Genet 1999 Jul
PMID:The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus. 1036 64

A thyrotrophin (TSH) binding site has been identified on the extracellular domain of the human thyrotrophin receptor (hTSHR) using monoclonal antibodies that recognise the native hTSHR. These antibodies were produced by immunising BALB/c mice with denatured recombinant material, selected by their reaction with recombinant hTSHR expressed on heterologous cell lines using flow cytofluorimetric analysis, and characterised by immunoblotting and immunoprecipitation. The epitopes the monoclonal antibodies recognise were determined using multiple overlapping synthetic peptides. All of the antibodies reacted with epitopes within the region 335-390; these epitopes must be accessible on the external surface of the native hTSHR. None of the antibodies stimulated cAMP production of recombinant hTSHR cell lines. The epitopes of two antibodies (residues 337-342 and 355-358) are in the small peptide thought to be removed by proteolytic processing of hTSHR. A further five different antibodies (determined from their variable region sequences) all reacted with residues 381-384 emphasising the immunogenicity of this region. The functional importance of residues 381-384 as a TSH binding site was shown by the fact that some of these monoclonal antibodies caused inhibition of radiolabelled TSH binding of 80-90% at 1 microg/ml and greater than 50% inhibition at 0.1 microg/ml (0.65 nM--i.e. comparable in effectiveness with TSH itself). Residues 381-384 may form part of the target regions recognised by inhibitory autoantibodies found in Graves' disease.
Mol Cell Endocrinol 1999 Mar 25
PMID:Identification of an important thyrotrophin binding site on the human thyrotrophin receptor using monoclonal antibodies. 1037 31

Graves disease is complex autoimmune thyrotoxicosis. A number of genes may contribute to the development of the disorder. Some of them may be genes that encode cytotoxic T-lymphocyte-associated serine esterase-4 (CTLA4), subunit 2 of large multifunctional protease (LMP2), thyroid-stimulating hormone receptor (TSHR), and interleukin 1 receptor antagonist (IL1RN). We studied polymorphism of Ala17Thr CTLA4, H60R LMP2, Pro52Thr TSHR, and IL1RN-VNTR in healthy controls (n = 93) and patients with Graves disease (n = 78) using PCR. To study CTLA4, H60R, and TSHR polymorphism, PCR products were digested with MboI, Hin6I and PsyI, respectively. Comparative analysis using chi(2) test showed significant differences in allele and genotype frequency of Ala17Thr polymorphic marker between the two groups studied. Thus, the CTLA4 gene may be involved in the pathogenesis of Graves disease in a Moscow population.
Mol Genet Metab 2000 Jul
PMID:Complex association analysis of graves disease using a set of polymorphic markers. 1092 76

Basedow-Graves disease is an autoimmune thyroid syndrome. Genetic factors contribute to the pathogenesis of Graves disease, and current findings confirm that a number of genes may be involved in the development of autoimmune thyrotoxicosis. At present three loci, namely human leukocyte antigen (HLA, 6p21.3), cytotoxic T-lymphocyte-associated esterase-4 (CTLA4, 2q33), and thyroid-stimulating hormone receptor (TSHR, 14q31), are the only well-known genetic determinants for Graves disease. It is difficult to determine clearly the contribution of large multifunctional proteasome genes and transporter genes associated with antigen processing in the disorder, because of strong linkage disequilibrium between these genes and certain HLA alleles. Two recently discovered suspectibility loci, 20q11.2 and Xq21.33-q22, should be studied to find specific genes linked to Graves disease.
Mol Genet Metab
PMID:Genetic determinants of Graves disease. 1100 97

The transport of metabolites, coenzymes, and ions across the mitochondrial inner membrane is still poorly understood. In most cases, membrane transport is facilitated by the so-called mitochondrial carrier proteins. The yeast Saccharomyces cerevisiae contains 35 members of the carrier family, but a function has been identified for only 13 proteins. Here, we investigated the yeast carrier Leu5p (encoded by the gene YHR002w) and its close human homologue Graves' disease protein. Leu5p is inserted into the mitochondrial inner membrane along the specialized import pathway used by carrier proteins. Deletion of LEU5 (strain Deltaleu5) was accompanied by a 15-fold reduction of mitochondrial coenzyme A (CoA) levels but did not affect the cytosolic CoA content. As a consequence, the activities of several mitochondrial CoA-dependent enzymes were strongly decreased in Deltaleu5 cells. Our in vitro and in vivo analyses assign a function to Leu5p in the accumulation of CoA in mitochondria, presumably by serving as a transporter of CoA or a precursor thereof. Expression of the Graves' disease protein in Deltaleu5 cells can replace the function of Leu5p, demonstrating that the human protein represents the orthologue of yeast Leu5p. The function of the human protein might not be directly linked to the disease, as antisera derived from patients with active Graves' disease do not recognize the protein after expression in yeast, suggesting that it does not represent a major autoantigen. The two carrier proteins characterized herein are the first components for which a role in the subcellular distribution of CoA has been identified.
Mol Cell Biol 2001 Feb
PMID:The yeast mitochondrial carrier Leu5p and its human homologue Graves' disease protein are required for accumulation of coenzyme A in the matrix. 1115 96

Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is caused by multiple genetic and environmental factors. The clinical and immunological features of GD and HT are distinct; however, there are multiplex families with both GD and HT, and cases in which GD evolves into HT. Thus, there may be specific susceptibility loci for GD or HT, and common loci controlling the susceptibility to both GD and HT may exist. A genome-wide analysis of data on 123 Japanese sib-pairs affected with AITD was made in which GD- or HT-affected sib-pairs (ASPs) were studied to detect GD- or HT-specific susceptibility loci, and all AITD-ASPs were used to detect AITD-common susceptibility loci. Our study revealed 19 regions on 14 chromosomes (1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 18 and 22) where the multipoint maximum LOD score (MLS) was >1. Especially, chromosome 5q31-q33 yielded suggestive evidence for linkage to AITD as a whole, with an MLS of 3.14 at D5S436, and chromosome 8q23-q24 yielded suggestive evidence for linkage to HT, with an MLS of 3.77 at D8S272. These observations suggest the presence of an AITD susceptibility locus at 5q31-q33 and a HT susceptibility locus at 8q23-q24.
Hum Mol Genet 2001 Jun 15
PMID:Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto's thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese. 1144 Sep 90

Antithyroid drugs (ATD) are known to reduce 131I efficacy in thyrotoxicosis, though the underlying mechanism remains misunderstood. To study the impact of long term administration of carbimazole on both iodine stores (127I, secondary ion mass spectrometry microscopy) and targeting (125I, radioautography) at the intraglandular level in a woman who underwent surgery for Graves' disease. 125I distribution was dramatically heterogenous and large areas of the sample appeared poorly or no stained at all. This may correspond to flat follicles, hypofunctioning or ATD blocked ones and to the various histological changes related to the thyroiditis. SIMS counting showed huge variations of the interfollicular iodine stores (0 to 1.18 microg/mg) and lower mean values than those observed in nodular goiters. SIMS imaging depicted iodine free areas and others with preserved thyroglobulin synthesis, as assessed via 32S- mapping, but low to undetectable 127I, suggesting focal organification defects. Since ATD reduce iodine storage and uptake capabilities and enhance the iodine heterogeneity of interfollicular targeting, a related enhancement of the spatial 131I dose distribution is unavoidable. ATD may reduce 131I efficacy by variably reducing the number of follicles which can be actually or significantly targeted, e.g. irradiated (antirecruitement effect).
Cell Mol Biol (Noisy-le-grand) 2001 May
PMID:SIMS evidence that carbimazole enhances spatial heterogeneity of thyroid iodine storage and targeting in a woman with Graves' disease. 1144 59


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