Identification of a novel mutation in the gene encoding the β‐triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone

Mixson, A. James; Renault, Justine; Ransom, Stephen C.; Bodenner, Donald; Weintraub, Bruce D.

doi:10.1111/j.1365-2265.1993.tb00999.x

Cited by 45 publications

(28 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, REE showed a similar correlation with genotype, being more elevated in cases with markedly deleterious (type 1) TRβ mutations ( Figure 1G). It has also been suggested that a subgroup of TRβ mutations (R338W, R383H, and R383C) are associated with PRTH (18,19). However, mean REE in individuals harboring such mutations (R338W, R383H, A subgroup of RTH subjects (n = 13) also underwent chamber calorimetry, and BMR measurements (expressed per kg LBM) confirmed significantly raised energy expenditure (P = 0.0005) compared with age-, gender-, weight-, and BMI-matched control…”

Section: Characteristics Of the Rth Cohortmentioning

confidence: 99%

Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

Mitchell¹,

Savage²,

Dufour³

et al. 2010

J. Clin. Invest.

View full text Add to dashboard Cite

Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor β (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13 C/ 31 P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor α sensitivity to elevated thyroid hormone levels.

show abstract

Section: Characteristics Of the Rth Cohortmentioning

confidence: 99%

Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

Mitchell¹,

Savage²,

Dufour³

et al. 2010

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…Although THR was initially separated into three disorders (generalized resistance to thyroid hormone, selective pituitary resistance, and peripheral resistance to thyroid hormone), it is now thought that these three forms are not distinct but rather are part of a spectrum of resistance (2). Even within the same kindred, marked heterogeneity in the degree of resistance exists (2,3). Most cases of thyroid hormone resistance have evidence of both pituitary and peripheral resistance and exhibit an autosomal dominant mode of inheritance.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of mutant and normal beta T3 receptor alleles in kindreds with generalized resistance to thyroid hormone.

Mixson

Hauser²,

Tennyson³

et al. 1993

J. Clin. Invest.

View full text Add to dashboard Cite

Thyroid hormone resistance (THR) is primarily an autosomal dominant inherited disease characterized by resistance of pituitary and peripheral tissues to the action of thyroid hormone. We investigated whether the heterogeneous phenotypic features that occur not only among kindreds but also within the same kindred might be due to the expression of differing ratios of mutant and normal receptors in tissues. Using an allele-specific primer extension method, we determined the relative expression of normal and mutant mRNAs from the fibroblasts of affected and unaffected members of two kindreds with TRH: A-H and N-N. While two affected members of A-H, as expected, had nearly equal amounts of normal and mutant hTR(3 mRNA, two other members had mutant mRNA levels that accounted for at least 70% of the hTR# mRNA. Phenotypic variability within and between kindreds with generalized resistance to thyroid hormone GRTH may be due to this differential expression of the mutant and wild type mRNA. Furthermore, when several clinical parameters of THR were compared in several affected members from two kindreds with GRTH, we found that two cases in one kindred exhibited a high mutant-tonormal hTR68 ratio and had considerably more bone resistance during their development. In certain kindreds with THR, differing ratios of normal and mutant hTR receptors may be age and growth related and may account for the reported attenuation of phenotypic symptoms with age. (J. Clin. Invest. 1993.

show abstract

“…The mutation lies at nucleotide 1297 (C to T) in exon 7, which alters the 333 amino acid, arginine, to tryptophan [6,7]. In the present case, the result of SSCP, which is a simple and rapid method in detecting point mutations [14], suggested the existence of mutation(s) in exon 7 of the TRH gene of this patient.…”

Section: Discussionmentioning

confidence: 47%

“…Genetic analysis of the thyroid hormone receptor has provided the basis for further understanding of syndromes of thyroid hormone resistance [4,5]. In most cases, mutations in the T3 receptor /3 (TR f3) gene are clustered in exons 7 and 8, and have been reported in 28 families with GRTH and in 2 subjects with PRTH [3,6,7], although another point mutation is reported in a family with GRTH [8]. In this paper we report a case of resistance to thyroid hormone and discuss the distinction between GRTH and PRTH.…”

mentioning

confidence: 99%

A Case of Hyperthyroidism Due to Pituitary Resistance to Thyroid Hormone.

et al. 1994

View full text Add to dashboard Cite

Abstract. A fifteen-year-old male was admitted to our hospital because his thyroid function showed a lack of TSH suppression in the face of elevated thyroid hormone. This patient complained of heat intolerance, palpitation and hand tremor. Peripheral indices of thyroid hormone action indicated a hypermetabolic state. Serum TSH did not respond sufficiently to TRH stimulation, suggesting TSHsecreting pituitary adenoma. However, sellar CT scan and MRI images did not demonstrate any pituitary adenoma.Moreover, the serum TSH a-subunit concentration was not high and serum TSH was partially suppressed by the administration of T3. Furthermore, the results of single stranded conformation polymorphism (SSCP) suggested the existence of mutation(s) in the exon 7 of T3 receptor f3 (TRI3) gene of this patient. These findings support the diagnosis of pituitary resistance to thyroid hormone.

show abstract

Identification of a novel mutation in the gene encoding the β‐triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone

Cited by 45 publications

References 29 publications

Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

Differential expression of mutant and normal beta T3 receptor alleles in kindreds with generalized resistance to thyroid hormone.

A Case of Hyperthyroidism Due to Pituitary Resistance to Thyroid Hormone.

Contact Info

Product

Resources

About