Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Various point mutations in the c-erbA thyroid hormone receptor (TR) beta gene of unrelated kindreds have been reported to be responsible for different phenotypes of generalized thyroid hormone resistance. We now report a new point mutation, Td, in one of two TR beta alleles of three affected members of one family, designated family T. In contrast to the previously described point mutations, all located in the T3-binding domain of the TR beta gene, mutation Td was identified in the carboxy-terminal part of the hinge domain. Direct sequencing of the polymerase chain reaction-amplified whole coding region of the patients' fibroblast TR beta genes displayed a single guanine to adenine transition at cDNA nucleotide position 985. This altered alanine (GCC) to threonine (ACC) in codon 229. Garnier prediction of the consequence of the mutation indicated an altered secondary structure. The G----A nucleotide substitution was not present in 80 random TR beta alleles, suggesting that this point mutation is responsible for generalized thyroid hormone resistance in family T. The in vitro expressed mutant TR beta was shown to bind with high affinity to various thyroid hormone response elements. However, the affinity of the TR beta to bind to T3 was reduced 3-fold, indicating that the hinge domain of the TR beta is important for full ligand-binding activity. Moreover, it seems that multiple subdomains of the TR beta interact cooperatively to achieve optimal T3 activity.
Mol Endocrinol 1992 Jul
PMID:A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance. 132 20

Different point mutations have been identified in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene that are associated with variant phenotypes of generalized thyroid hormone resistance (GTHR). In most cases of GTHR, heterozygotes are affected; a single mutant allele results in the inhibition of the function of normal thyroid hormone receptors. We report here a novel genetic abnormality, a 3-basepair (bp) deletion in the T3-binding domain of the beta-receptor in a kindred, S, with GTHR. One patient, S1, was the product of a consanguineous union of two heterozygotes and was homozygous for this defect. Heterozygotes from kindred S harbored a CAC deletion at nucleotides 1295-1297, which resulted in the deduced loss of amino acid residue threonine at codon 332, and they displayed elevated free T4 levels and inappropriately normal TSH levels characteristic of other kindreds with GTHR. However, patient S1, who had two mutant alleles, had markedly elevated TSH and free T4 levels and displayed profound abnormalities in brain development and linear growth. A fibroblast c-erbA beta cDNA extending from codon 175 to stop codon 457 was cloned from patient S1, sequenced, and used to create a full-length mutant cDNA. The kindred S mutant receptor was synthesized in vitro and did not bind T3. This mutant receptor did bind with similar avidity as the wild-type human beta-receptor to thyroid hormone response elements of the human TSH beta (-12 to 43 bp) and rat GH (-188 to -160 bp) genes. Kindred S showed the effect in man of heterozygous and homozygous expression of a dominant negative form of c-erbA beta.
Mol Endocrinol 1991 Mar
PMID:A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. 165 89

An abnormal human thyroid hormone beta-receptor (hTR beta-Mf), which has a glycine to arginine substitution in the hormone-binding domain, has been identified in affected members of one family with generalized resistance to thyroid hormone. To better understand the mechanism by which this mutation produces the observed abnormality, expression vectors for the wild-type and mutant thyroid hormone receptors (TRs) were prepared to test hormone-binding activity and trans-activation function. Nuclear extracts of COS-7 cells transfected with wild-type TRs showed specific T3-binding activity, while mutant receptor-transfected COS-7 nuclear extract failed to bind T3. On the other hand, in a avidin-biotin complex DNA-binding assay, in vitro translated hTR beta-Mf showed high binding activity to the thyroid hormone response element, which was indistinguishable from that of wild-type TRs. In a transient expression study, only the wild-type TRs activated a rat GH gene promoter-chloramphenicol acetyltransferase fusion gene in a T3-dependent manner. Additionally, when wild-type TR and hTR beta-Mf were cotransfected, hTR beta-Mf inhibited gene activation regulated by wild-type TRs. From these results we conclude that 1) hTR beta-Mf has no demonstrable T3 binding and appears to have minimal, if any, ability to activate a thyroid hormone-responsive gene in spite of its preserved ability to bind to a TRE in DNA; 2) hTR beta-Mf inhibits the transcriptional activation of a thyroid hormone-responsive gene by the wild-type TRs in a dominant manner; and 3) the dominant negative regulatory function of hTR beta-Mf appears to explain the clinical manifestations of thyroid hormone resistance produced by this mutation when present in the heterozygous state.
Mol Endocrinol 1990 Dec
PMID:Dominant negative transcriptional regulation by a mutant thyroid hormone receptor-beta in a family with generalized resistance to thyroid hormone. 208 93

The thyroid hormones and retinoic acid are potent modulators of differentiation, development, and gene expression. The transcriptional activities of these ligands are mediated by closely related nuclear receptors which bind and activate identical hormone responsive DNA elements. We noticed that a region within the ligand binding or E domain is well conserved between receptors for these hormones. This region contains hydrophobic heptad repeats that are structurally similar to the leucine-zipper dimerization domain. To study the function of this conserved domain, we examined the transcriptional responses of thyroid hormone receptor/c-erbA deletion mutants which lacked the heptad repeats. We previously reported that the chick c-erbA-alpha possesses hormone-independent (constitutive) activity in cells which express endogenous rat thyroid hormone receptor. We now demonstrate that this activity is abolished upon deletion of the conserved heptad repeats. This suggests that the heptad repeats mediate in vivo interactions between chick c-erbA and rat thyroid hormone receptors. To further test this hypothesis deletion mutants of chick c-erbA were constructed which contained all eight heptad repeats but which lacked the zinc-finger DNA binding domain. Although these mutants are transcriptionally inactive, they act in a dominant-negative fashion to block trans-activation by both the chick c-erbA-alpha and the endogenous thyroid hormone and retinoic acid receptors. We suggest that the heptad repeats mediate the formation of inactive mutant/wild-type hetero-dimers. Dimer formation suggests a mechanism to account for the dominant-negative phenotypes displayed by nonhormone binding variants of c-erbA, the proto-oncoprotein v-erbA and patients with the generalized thyroid hormone resistance syndrome.
Mol Endocrinol 1989 Oct
PMID:A domain containing leucine-zipper-like motifs mediate novel in vivo interactions between the thyroid hormone and retinoic acid receptors. 255 97

Multiple cDNAs belonging to the c-erbA gene family encode proteins that bind T3 with high affinity. However, the biological functions of these multiple thyroid hormone receptors have not yet been clarified. Generalized thyroid hormone resistance (GTHR) refers to a human syndrome characterized by tissue refractoriness to the action of thyroid hormones; several studies have suggested quantitative or qualitative defects in T3 binding to nuclear receptors in certain kindreds. To investigate the biological functions of the c-erbA genes, c-erbA alpha and c-erbA beta, we tested the hypothesis that an abnormal c-erbA gene product is present in GTHR by examining these genes in members of one kindred. Restriction enzyme analysis failed to identify an abnormal pattern in affected individuals suggesting no rearrangements or large deletions. However, we demonstrated that the gene conferring the GTHR phenotype is tightly linked to the c-erbA beta locus on chromosome 3. This linkage strongly suggests that the c-erbA beta gene is important in man as a thyroid hormone receptor and identifies a putative c-erbA beta mutant phenotype with central nervous system, pituitary, liver, metabolic, and growth abnormalities.
Mol Endocrinol 1988 Dec
PMID:Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene. 290 63

Unlike the steroid hormone receptors that bind their response elements as homodimers, thyroid hormone receptor (TRs) as well as retinoic acid receptors and several other receptors have been shown to require heterodimerization with retinoid X receptors (RXR) for efficient binding to most response elements. In this article we have compared in detail TR DNA binding and its gene-regulatory characteristics in the presence and absence of RXR. We observe that in the absence of RXR, TRs are able to bind with high affinity as homodimers to a subset of thyroid hormone response elements consisting of two AGGTCA motifs arranged as inverted palindromes. This binding is inhibited by T3, which prevents TR homodimers from functioning as ligand-dependent transcriptional activators. We demonstrate that TR homodimers can act as potent ligand-responsive repressors, in particular when binding to sites 3' of the TATA box. Thus, TRs appear to have important regulatory functions in the absence of RXRs. This is strongly supported by our observations that some naturally occurring TR beta mutants that have been associated with generalized thyroid hormone resistance as well as the v-erbA oncogene are defective in this activity. Thus ligand-sensitive repression by TRs is an important regulatory mechanism.
Mol Endocrinol 1995 May
PMID:Thyroid hormone receptor homodimers can function as ligand-sensitive repressors. 756 4

The multiplicity of thyroid hormone (TH) effects appears to be mediated by two TH receptors (THRs) encoded by two genes, alpha and beta, and, perhaps, by their various isoforms. The expression of THR beta is correlated with the presence of high affinity binding sites for TH, and all the mutations which cause the syndrome of generalized thyroid hormone resistance occur in THR beta. The function of THR alpha has not been clearly defined as yet. Another enigma in TH action is the effect on the testis. It has been shown that the testis of the adult rat does not respond to TH as measured by an increase in oxygen consumption. Furthermore, it has not been possible to demonstrate the presence of a nuclear high affinity binding site for TH in adult testis. To resolve these problems were measured the levels of THR alpha, its nonhormone binding variant, and THR beta mRNA in the testis at various stages of development. We discovered that the beta-message is absent at all times, whereas the alpha-message is expressed only from fetal through prepubertal stages and is absent in adult testis. THR alpha, but not the beta-mRNA, was detected in immature Sertoli cells in culture, and neither was found in adult Sertoli cell-enriched cultures. Furthermore, THR alpha and its variant mRNA was found, using in situ hybridization, in the seminiferous cords and seminiferous tubules of fetal and prepubertal testis.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1994 Jan
PMID:Developmental regulation of the thyroid hormone receptor alpha 1 mRNA expression in the rat testis. 815 33

Generalized resistance to thyroid hormone (GRTH) is a disorder of thyroid hormone action which has been linked to the beta thyroid hormone receptor (TR beta) gene. A diverse array of TR beta mutations have been characterized, and these distinct genotypes have been associated with characteristic patterns of severity and tissue distribution of clinical thyroid resistance. In this report, we describe a patient with GRTH caused by a single C-->A base mutation (nucleotide 1623) in one allele of TR beta (exon 10). The mutation produces a premature translation termination signal (UGA) at codon 446 and predicts expression of a mutant TR beta which is truncated by 16 carboxyl-terminal amino acids (TR beta delta 446-461). This sequence was absent in both parents, indicative of a de novo mutation in the proband. To our knowledge, this case represents the first description of a mutation producing premature translation termination of TR beta in association with the syndrome GRTH, and emphasizes the critical role of the carboxyl terminal region of TR beta in mediating both positive and negative regulation of thyroid-responsive target genes in many tissues.
Mol Cell Endocrinol 1994 Feb
PMID:Generalized thyroid hormone resistance due to a deletion of the carboxy terminus of the c-erbA beta receptor. 818 64

C-erbA receptors and v-erbA have been shown to functionally interact with 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-inducible gene expression. These proteins enhance trans-activation by c-jun, and the c-erbA receptors in the presence of thyroid hormone repress TPA and c-jun induction of transcription. Also, v-erbA can abrogate T3-mediated repression. We have examined how dominant negative (S and CL) and nondominant negative (G-H) receptors cloned from various patients with thyroid hormone resistance syndromes affect expression of the collagenase promoter induced with TPA. The CL receptor (ARG315HIS mutation) has a 2-fold reduction in T3-binding affinity compared with human c-erbA beta 1 wild-type (WT) receptor, whereas the G-H receptor (ARG311HIS) and S receptor (deletion, THR codon 332) have T3-binding affinities reduced by 100-fold and greater than 100-fold, respectively. These mutant receptors were cotransfected with a collagenase promoter (-1200 to +63 base pairs) chloramphenicol acetyltransferase reporter gene (Col-CAT) into COS-7 cells. Levels of CAT reporter gene expression after transient transfection were determined in the presence or absence of 3-10 nM T3 and the presence or absence of 100 nM TPA. Unoccupied CL receptor and G-H and S receptors stimulated TPA-induced Col-CAT expression 1.5- to 9-fold. The CL receptor with thyroid hormone totally repressed TPA induction of the collagenase receptor. In the presence of thyroid hormone, the enhancing effects by S and G-H receptors on TPA-induced Col-CAT expression were unaffected and minimally diminished, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1993 Sep
PMID:Dominant and nondominant negative C-erbA beta 1 receptors associated with thyroid hormone resistance syndromes augment 12-O-tetradecanoyl-phorbol-13-acetate induction of the collagenase promoter and exhibit defective 3,5,3'-triiodothyronine-mediated repression. 824 13

Luteinizing hormone (LH) supports steroidogenesis and maintains testicular and ovarian function. Mediators of LH action exert homologous regulation of membrane receptors, steroidogenic enzymes and other regulatable genes of the Leydig cell (LC). Androgen and estrogen induced by LH could act through its cognate receptors in the LC to regulate gene expression. Although androgens are unquestionable essential for spermatogenesis and presumably exert their heterologous action through androgen receptors present in the Sertoli its regulatory mechanism in germinal cell maturation is far from clear. In contrast to physiological concentrations of gonadotropins which maintain the steroidogenic functions and LH and prolactin receptors in the gonads, high concentrations of gonadotropin (hCG) cause receptor down-regulation and desensitization of steroidogenic enzymes of the LCs in vivo (3beta-hydroxysteroid dehydrogenase types I and II, 17alpha-hydroxylase/17,20 lyase, and 17beta-hydroxysteroid dehydrogenase type III [17beta-HSD]). In addition, 17beta-HSD is regulated by compartmentalized endogenous glucose/ATP. The attenuation of steroidogenesis which results from receptor mediated activation by cognate hormone, but is independent of the subsequent phase of receptor down-regulation, is due to changes at the transcriptional level. Among the candidates affecting this regulation are active steroid metabolites (direct or indirect of steroids and other mediator(s) i.e. cAMP, putative transcription factors induced by LH action). Differential display assay revealed another gene which is transcriptionally regulated by gonadotropin termed GRTH (Gonadotropin Regulated Testicular Helicase). GRTH is a novel member of the DEAD-box family of RNA helicases, and is specifically expressed in LCs and meiotic LC of the testis. It is markedly up-regulated by hCG via cAMP-induced androgen formation in LCs at doses that cause down-regulation of receptors and steroidogenic enzymes. GRTH functions as a translational activator. Androgen produced by gonadotropin stimulation exerts intracrine/autocrine actions on GRTH, and also could influence transcription within the seminiferous tubule. GRTH may contribute to the control of steroidogenesis, including the restoration of down regulated cellular functions, and in the paracrine regulation of androgen dependent gene(s) involved in the meiotic process, and could thus have a crucial role in spermatogenesis.
J Steroid Biochem Mol Biol
PMID:Regulation of steroidogenic enzymes and a novel testicular RNA helicase. 1138 77


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