Thyroid hormone resistance syndrome with P453T mutation in thyroid hormone receptor ß gene: A pedigree report.

RATIONALE: Thyroid hormone resistance syndrome (THRS) is an inherited condition characterized by reduced responsiveness of target tissues to thyroid hormone. Due to their nonspecific symptomatic manifestations, these patients can be misdiagnosed. This study reports a pedigree with THRS caused by a mutation in the thyroid hormone receptor ß (THRß) gene. PATIENT CONCERN: The proband, a 36-year-old woman at 19+4 weeks of gestation, was referred to our hospital because of abnormal thyroid function results. She was diagnosed with hyperthyroidism in October 2015, and had been treated with methimazole until her pregnancy. DIAGNOSIS: The proband and 2 of her children were diagnosed with THRS based on genetic analysis. Sequence analysis of the THRß gene showed a heterozygous mutation C>A located at exon 10. The mutation results in a change in proline for threonine at amino acid position 453, P453T. INTERVENTIONS: No treatment will fully and specifically correct the defect. All 3 patients were in normal metabolic status, and thus treatment was not required. OUTCOMES: During a 2-year follow-up period, none of them had any complaints. The 20-year-old son (167 cm in height) and the 18-year-old daughter (150 cm in height) both had low academic performance. LESSONS: Elevated serum thyroid hormone (TH) levels associated with nonsuppressed thyroid-stimulating hormone (TSH) levels usually leads to the diagnosis of THRS. Genetic analysis provides a short cut to diagnosis and the treatment should be based on the patient's clinical manifestations.

A Direct Comparison of Thyroid Hormone Receptor Protein Levels in Mice Provides Unexpected Insights into Thyroid Hormone Action.

Background: Thyroid hormone (TH) action is mediated by three major thyroid hormone receptor (THR) isoforms α1, ß1, and ß2 (THRA1, THRB1, and THRB2). These THRs and a fourth major but non-TH binding isoform, THRA2, are encoded by two genes Thra and Thrb. Reliable antibodies against all THR isoforms are not available, and THR isoform protein levels in mammalian tissues are often inferred from messenger RNA (mRNA) levels. Methods: We generated knock-in mouse models expressing endogenously and identically 2X hemagglutenin epitope (HA)-tagged THRs (THRA1/2, THRB1, and THRB2), which could then be detected by commercially available anti-HA antibodies. Using nuclear enrichment, immunoprecipitation, and Western blotting, we determined relative THR protein expression in 16 mouse organs. Results: In all peripheral organs tested except the liver, the predominant THR isoform was THRA1. Surprisingly, in metabolically active organs such as fat and muscle, THRB1 protein levels were up to 10 times lower than that of THRA1, while their mRNA levels appeared similar. In contrast to peripheral organs, the central nervous system (CNS) had a unique pattern with relatively low levels of both THRB1 and THRA1, and high levels of THRA2 expression. As expected, THRB2 was highly expressed in the pituitary, but a previously unknown sex-specific difference in THRB2 expression was found (female mice having higher pituitary expression than male mice). Higher THRB2 expression appears to make the central axis more sensitive to TH as both serum thyrotropin and Tshb mRNA levels were lower in female mice. Conclusions: Direct comparison of THR protein abundance in different organs using endogenously tagged HA-THR mouse lines shows that expression of THR isoforms is regulated at transcriptional and posttranscriptional levels, and in organ-specific manner. The prevalence of THRA1 and low abundance of THRB1 in majority of peripheral tissues suggest that peripheral actions of these isoforms should be revisited. A unique pattern of high THRA2 in CNS warrants further exploration of this non-TH binding isoform in brain development. Finally, THRB2, in addition to cell-specific control, is also regulated in a sex-specific manner, which may change the hypothalamus-pituitary-thyroid axis set point and perhaps metabolism in males and females.

Comparative endocrine disruptive effects of contaminants in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea.

We investigated variables related to thyroid, vitamin A and calcitriol homeostasis, immune function and tumour development in ringed seals (Phoca hispida) from the polluted Baltic Sea and a less polluted reference location at Svalbard, Norway. We also examined the relationships between the biological variables and the concentrations of persistent organic pollutants (POPs) and their hydroxylated (OH) metabolites. Our data show higher plasma concentrations of free triiodothyronine (T3), and ratios of free and total T3 in Baltic seals as compared to Svalbard seals. Baltic seals had also higher hepatic mRNA expressions of deiodinase-I, thyroid hormone receptor beta, retinoic acid receptor alpha, growth hormone receptor and interleukin-1beta compared to Svalbard seals. Levels of plasma retinol were lower in the Baltic seals as compared to Svalbard seals. No geographical difference was observed for other thyroid hormone levels and hepatic retinoid levels. Ratios of free and total T3 were positively correlated to OH-POPs in plasma. The results of the present study suggest that endocrine homeostasis may be affected by contaminant and metabolite exposure in the Baltic ringed seals with respect to circulating hormones and retinol and hepatic mRNA expressions. In addition, OH-POPs may putatively produce the disruption of thyroid hormone transport in plasma.