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V K Chatterjee

Publications and source records attributed to V K Chatterjee.

At least 55 records · Page 3Linked to original sources
PubMed1997

[Thyroid hormone resistance: variable clinical manifestations in five patients].

AIM: The syndrome of thyroid hormone resistance (RTH) is characterised by elevated circulating thyroid hormones, unsuppressed TSH levels and peripheral refractoriness to hormone action. Patients with RTH may be clinically hyperthyroid if the pituitary gland is more insensitive than other tissues to thyroid hormones. More often, patients have peripheral tissue resistance as well and are euthyroid. RTH is related to point mutations in the T3-binding domain of the beta-receptor gene. We report the variable clinical and biochemical features of five patients with RTH. METHODS: Five patients with RTH were clinically and biochemically evaluated: thyroid tests were done at baseline, after TRH stimulation and after T3-suppression test. Thyroid ultrasound was performed as well. Individual exons of the thyroid hormone receptor beta gene were amplified from leucocyte DNA in these patients using the polymerase chain reaction (PCR). RESULTS: Sequence analysis identified a single point mutation at a certain nucleotide position. This corresponds to aminoacids substitutions at one position in the predicted aminoacid sequence. RTH was familial in three individuals and sporadic in two. Three of the patients underwent thyroid surgery or radioiodine treatment because of recurrent goiter and/or "refractory hyperthyroidism". Moreover, one of our patients with RTH developed also hyperthyroidism due to Graves disease and underwent thyroid surgery for the third time. Her brother, besides RTH, demonstrated strongly positive TPO-antibodies and a hypoechogenic pattern on ultrasound. So the diagnosis of Hashimoto's thyroiditis was made. CONCLUSIONS: RTH has to be considered in all patients with inappropriate TSH secretion. The clinical manifestation of patients with RTH is heterogenous. Thyroid antibody measurements should be performed regularly in order to detect the development of coexisting autoimmune thyroid disease.

Adult↗
PubMed1994

Functional analysis of a transactivation domain in the thyroid hormone beta receptor.

Hormone-dependent transcriptional activation (AF-2) by the thyroid hormone beta receptor (TR beta) localizes to its carboxyl-terminal domain. A putative transactivation sequence within this domain was analyzed by mutating individual residues to alanine. Mutant receptor carboxyl-terminal domains were tested coupled to the heterologous DNA binding domain of Gal4. A single mutant receptor (E460A) showed normal hormone binding and activation, whereas several others (P453A, F455A, L456A, F459A) exhibited impaired transactivation which correlated with their reduced ligand binding. Two mutations (L454A, E457A) were able to dissociate these properties, generating transcriptionally defective mutant proteins with preserved hormone binding. A further conservative substitution (E457D) was also nonfunctional, and these three mutations were equally deleterious when tested in the context of full-length TR beta with a natural thyroid hormone response element containing promoter. This loss of activity was not due to altered DNA binding or expression of mutant receptors in cultured cells. They also retained the ability to recruit VP16-tagged retinoid X receptor in vivo as well as bind the basal transcription factors TFIIB and TBP in vitro. Our observations indicate that conserved hydrophobic (Leu454) and charged (Glu457) residues mediate AF-2 activity of TR beta, possibly via a co-activator that has yet to be identified.

Amino Acid Sequence↗
PubMed1994

Hormone-nuclear receptor interactions in health and disease. Thyroid hormone resistance.

The syndromes of resistance to thyroid hormone (RTH) are rare disorders characterized by elevated levels of circulating free thyroid hormones, inappropriate TSH secretion and variably reduced peripheral tissue responses to iodothyronine action. On the basis of clinical features, two major forms of RTH are recognized: generalized resistance (GRTH) in which patients are asymptomatic with few clinical signs, and pituitary resistance (PRTH) where patients present with features associated with thyrotoxicosis. However, a review of the literature and our own experience indicates that there is a wide overlap of clinical and biochemical features between individuals with GRTH or PRTH. Genetic analysis shows that both disorders are associated with a number of different mutations in the thyroid hormone receptor beta (TR-beta) gene which localize to two regions in the hormone-binding domain. The mutant proteins are transcriptionally impaired but preserve the ability to bind DNA, dimerize and inhibit the function of their wild-type counterparts in a dominant negative manner. Dominant negative effects of mutant receptors within the pituitary-thyroid feedback axis generate abnormal thyroid function test results characteristic of RTH. The variable peripheral resistance may be related to differences in tissue distribution of TR-alpha versus TR-beta receptor isoforms, variable dominant negative effects of mutant receptors on different target genes or other factors not related to the receptor mutation. Although GRTH and PRTH represent the variable phenotypic spectrum of a single genetic entity, this clinical distinction will remain useful as a guide to appropriate treatment.

Diagnosis, Differential↗
PubMed1994

The variable clinical phenotype in thyroid hormone resistance syndrome.

Thyroid hormone resistance syndrome (RTH) is a rare disorder characterized by elevated levels of circulating free thyroid hormones, inappropriate TSH secretion, and reduced peripheral tissue responses to iodothyronine action. On the basis of clinical features, at least two different forms of RTH have been described: generalized resistance (GRTH) in which patients are asymptomatic with few clinical signs and pituitary resistance (PRTH) where patients present with some signs and symptoms associated with thyrotoxicosis. However, a review of the literature and our own experience indicates that there is a wide overlap of symptoms and signs exhibited by individuals with GRTH or PRTH. Assessments using biochemical and physiological indices of thyroid hormone action are useful, but limited by their lack of precision and also show an overlap between values recorded in GRTH and PRTH. In addition, we have observed significant temporal variations in clinical signs as well as in parameters of thyroid hormone action in the same individuals, with no correlation with their subjective symptoms. Recent genetic analyses indicate that patients with either GRTH or PRTH are heterozygous for mutations in the thyroid hormone receptor beta (TR beta) gene. Indeed, different clinical features have been observed in affected individuals within a kindred harboring the same Tr beta mutation, and identical mutations have been identified in unrelated kindreds classified as GRTH or PRTH. These data support the view that GRTH and PRTH are variable manifestations of a single genetic entity. Nevertheless, this clinical distinction will remain useful as a guide to the most appropriate treatment. The variable phenotypic spectrum of thyroid hormone resistance may be related to factors other than mutations in Tr beta that have yet to be elucidated.

Diagnosis, Differential↗
PubMed1994

Spectrum of transcriptional, dimerization, and dominant negative properties of twenty different mutant thyroid hormone beta-receptors in thyroid hormone resistance syndrome.

Resistance to thyroid hormone (RTH) is usually dominantly inherited and characterized by elevated thyroid hormone levels, impaired feedback inhibition of pituitary TSH production, and variable hormonal responsiveness in peripheral tissues. We have identified 20 different mutations in the thyroid hormone beta-receptor (TR beta) gene in RTH and assayed mutant receptor properties using the TSH alpha subunit gene promoter or promoters containing three different types of positive thyroid response element (TRE). Dominant negative inhibition of wild type TR beta action by mutant receptors was also tested. The mutant receptors exhibited differing transcriptional inhibitory properties and dominant negative potential with the TSH alpha promoter that correlated with their impaired hormone binding, whereas transactivation and dominant negative effects with promoters containing positive TREs varied depending on their configuration. Heterodimeric mutant receptor-retinoid X receptor (RXR) interactions, either in cultured cells or as TRE-bound complexes in gel retardation assays, were uniformly preserved, whereas homodimeric receptor interactions could not be detected in vivo, and in vitro homodimer formation on TREs was variably reduced or absent for some mutant proteins. We correlate these findings with the distribution of receptor mutations that cluster in two areas within the hormone binding domain outside putative dimerization regions and show that artificial mutations that impaired heterodimerization abrogated dominant negative activity. Therefore, we suggest that the dominant negative effect of mutant receptors in the pituitary-thyroid axis generates the characteristic biochemical abnormality of RTH and that variable resistance in other tissues may be due to response element-dependent differences in their dominant negative potential.

Amino Acid Sequence↗
PubMed1994

Treatment of Graves' disease with the block-replace regimen of antithyroid drugs: the effect of treatment duration and immunogenetic susceptibility on relapse.

Antithyroid drugs are commonly used as first-line treatment for Graves' disease, but the optimum regimen for inducing remission remains unclear. We gave the block-replace regimen of carbimazole plus thyroxine to 100 patients for 6 or 12 months, to determine whether prolonged treatment is associated with fewer relapses. The remission rate one year after cessation of treatment was 59% with the 6 month course and 65% with 12 months; this was not significantly different. We also analysed HLA markers identified by restriction fragment length polymorphisms and could not confirm the recently reported associations of outcome with HLA-DR4 or with an HLA-DQA2 allele. These results show that six months treatment with a block-replace regimen of antithyroid drugs is probably sufficient, in the UK, to achieve maximum remission of Graves' disease and that there are no HLA markers which clearly predict outcome.

Adult↗
PubMed1994

Resistance to thyroid hormone--an uncommon cause of thyroxine excess and inappropriate TSH secretion.

Resistance to thyroid hormone (RTH) is an uncommon inherited cause of hyperthyroxinemia with inappropriate TSH secretion. The syndromes are characterized by reduced target tissue responsiveness to circulating free thyroid hormones. The differential diagnosis to other diseases with similar laboratory results (high T4 with normal TSH) like familial dysalbuminemia or antibodies against iodothyronines or TSH is now possible with the appropriate use of new assays for free thyroid hormones. In the presence of thyrotoxic symptoms it may be difficult to differentiate the syndrome from a TSH-secreting pituitary tumour. Familial occurrence and a normal TSH-response to TRH that can not be suppressed by T3 are characteristic features of RTH, that may be helpful in that respect. The majority of RTH cases are dominantly inherited and have highly variable clinical signs and symptoms. There are, however, mainly two forms of the syndrome that have been shown to overlap clinically and biochemically, namely a generalised resistance (GRTH) and a more "selective" pituitary resistance to thyroid hormones (PRTH). The absence of thyrotoxic symptoms rather suggests GRTH, whereas thyrotoxic signs seem to be characteristic for PRTH. Following the cloning of thyroid hormone receptors, familial GRTH was shown to be tightly linked to the TR-(Thyroid hormone receptor)-beta gene locus. Molecular genetic studies have shown that even within a single kindred the same receptor mutation was associated with both, GRTH or PRTH, and therefore suggest that these two forms represent part of a variable clinical spectrum of a single genetic disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis, Differential↗
PubMed1993

Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone.

We report a woman with primary amenorrhoea and infertility associated with an isolated deficiency of pituitary follicle-stimulating hormone (FSH), but normal luteinizing hormone (LH) secretion. Ovulation was induced by administration of exogenous FSH and resulted in a successful pregnancy. Sequence analysis of the FSH beta-subunit gene indicated that she is homozygous for a two nucleotide frameshift deletion in the coding sequence. Her mother and son are heterozygous for this mutation. This deletion results in an alteration of amino acid codons 61-86 followed by a premature termination codon. The predicted truncated beta-subunit peptide lacks regions which are important for association with the alpha subunit and for binding to and activation of the FSH receptor. Abnormalities of FSH structure or function might be an under recognised but treatable cause of infertility.

Adult↗
PubMed1992

Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome.

OBJECTIVE: We wished to ascertain whether a mutation in the thyroid hormone receptor beta gene was present in a family with generalized thyroid hormone resistance syndrome and to characterize the functional properties of this mutant receptor. DESIGN: Blood samples were obtained from family members for hormone assays and genomic DNA was isolated from leucocytes for genetic analyses. PATIENTS: Three members (B,C,E) of a family with possible thyroid hormone resistance and two normal family members (A,D) were studied. MEASUREMENTS: Basal thyroid function tests together with serum sex hormone binding globulin (SHBG) levels were measured. The thyroid hormone receptor beta gene was amplified using the polymerase chain reaction and the receptor mutation identified by sequence analysis. The ability of mutant receptor to bind T3, interact with a specific DNA sequence and to modulate target gene expression was tested. The effects of mutant receptor on co-expressed wild type receptor action were determined. RESULTS: Patients with resistance had raised levels of T4 and T3 together with inappropriately normal serum TSH and SHBG whereas unaffected individuals had a normal hormone profile. A single nucleotide substitution corresponding to a glycine to serine mutation at codon 340 (G340S) in the hormone binding domain was identified in one of the two beta receptor gene alleles in patients with resistance, but not in the normal family members. When expressed in vitro, this receptor protein (G340S), as well as a related (G340R) mutant identified in another family, retained the ability to bind to a specific DNA sequence but were unable to bind ligand or to activate or repress target gene expression. In addition both receptor mutants were capable of inhibiting the function of wild type thyroid hormone receptor in a co-expression assay but differed in their inhibitory potential. CONCLUSIONS: We report a second type of mutation (Gly to Ser) in codon 340 of hTR beta in a family with generalized thyroid hormone resistance. Mutations at this site eliminate T3 binding, causing a loss of hormone-stimulated receptor function. However, the mutant receptors retain the ability to block normal receptor action. The occurrence of different mutations at the same site suggests that alterations in this region of the receptor may be important for generating the clinical phenotype of this disorder.

DNA Mutational Analysis↗
PubMed1992

Thyroid hormone receptors and their role in development.

That most major physiological actions of thyroid hormones could be mediated via hormonal regulation of gene expression has been known for more than 25 years. The localization of TR in the cell nucleus, first reported almost 20 years ago, confirmed this concept. But it is only since the cloning of the TR gene and its identification as the c-erbA oncogene, accomplished 6 years ago, that we have begun to understand the details of the interaction between the hormone and its receptor and between the receptor and its target gene. Perhaps the most significant concept to emerge from the molecular studies is that the TR belongs to the superfamily of nuclear receptors for steroid hormones and morphogens such as retinoids. It highlights the evolutionary conservation of a major network of cellular signalling and intracellular regulatory pathways and which has helped bring us closer to a unified concept of the action of many growth and developmental hormones. Several important questions to be solved in the future become obvious from this brief review of the role of thyroid hormone in regulating developmental processes. Among these is the explantation for the high degree of tissue specificity of hormonal regulation of gene expression. The discovery of differential expression of the two major TR genes and the generation of multiple isoforms of the receptor by alternate splicing go some way to answering this question, but this is clearly not the sole factor determining tissue specificity. It will be most important to find out more about the interaction between the receptor and other transcription factors or nuclear proteins, some of which may be tissue specific and others expressed ubiquitously. The autoinduction of TR during amphibian metamorphosis, described above, emphasizes the intriguing question of how receptor genes are regulated during development. We know little as yet about the promoters and regulatory factors involved in this process. Finally, we have also described the recent recognition of genetic defects in TRs that underlie thyroid hormone linked diseases in humans. Future studies on the molecular genetics of receptors will enhance the importance in clinical practice of receptor linked diseases.

Amino Acid Sequence↗
PubMed1991

Functional properties of human thyroid hormone receptor beta 1 overexpressed using baculovirus.

We have overexpressed the human beta 1 thyroid hormone receptor in insect cells using a recombinant baculovirus to a level of 5-10% of total cellular protein. The recombinant protein migrates as a 50 kDa band by SDS-PAGE and Western blot analysis. The expressed receptor binds to L-T3 with a Kd of 1.3 +/- 0.4 x 10(-10) M and to thyroid hormone analogues with an affinity hierarchy of TRIAC greater than L-T3 greater than L-T4 greater than rT3. Gel retardation assays show highly specific receptor binding to a TRE which is modified by the presence of ligand and avidin-biotin complex DNA analysis shows a Kd of 6.2 +/- 2.0 x 10(-10) M for this interaction. These results indicate high level expression of hTR beta with authentic hormone and DNA binding properties.

Animals↗
PubMed1991

Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors.

Thyroid hormone (T3) resistance is inherited in most cases in an autosomal dominant manner. The disorder is characterized by elevated free thyroid hormone levels and partial resistance to thyroid hormone at the cellular level. Distinct single amino acid substitutions in the ligand binding domain of the beta form of the thyroid hormone receptor have been described in two kindreds with this disorder. We used transient expression assays to characterize the functional properties of these receptor mutants, one containing a Gly to Arg change at amino acid 340 (G340R) and the other a Pro to His change at amino acid 448 (P448H). A nine amino acid carboxy terminal deletion (delta 448-456), analogous to an alteration that occurs in v-erbA, was also studied for comparison with the mutations that occur in the T3 resistance syndrome. None of the receptor mutants were able to mediate thyroid hormone dependent activation (TreTKCAT) or repression (TSH alpha CAT) of reporter genes when compared with the wild type receptor. In addition, the mutants inhibited the activity of normal alpha and beta receptor isoforms when examined in coexpression assays. This activity, referred to as dominant negative inhibition, was manifest with respect to both the positively and negatively regulated reporter genes. Although mutant receptor binding to DNA was unaffected, ligand binding studies showed that the G340R and delta 448-456 mutants failed to bind T3, whereas the P448H mutant bound hormone with reduced affinity (approximately 10% of normal) compared to the wild type receptor. Consistent with this finding, the P448H mutant receptor was partially active at higher T3 concentrations. Furthermore, the dominant negative inhibition elicited by the P448H receptor mutant at higher T3 concentrations was reversed in the presence of high doses of T3. These findings indicate that mutant beta receptors in patients with thyroid hormone resistance have reduced affinity for T3 and are functionally deficient, but impair the activity of normal receptors, thereby providing a mechanism for the dominant mode of inheritance in this disorder.

Base Sequence↗