Selenocysteine insertion sequence binding protein 2 (Sbp2) in the sex-specific regulation of selenoprotein gene expression in mouse pancreatic islets.

Selenoproteins are a group of selenocysteine-containing proteins with major roles in cellular antioxidant defense and thyroid hormone metabolism. Selenoprotein expression is determined by hierarchical mechanisms that result in tissue-specific levels. Current data inadequately explain the abundance of various selenoproteins under normal and pathological conditions, including in pancreatic ß-cells. Selenocysteine insertion sequence binding protein 2 (SBP2) is a critical protein in selenoprotein translation that also plays an essential role in stabilizing selenoprotein transcripts by antagonizing nonsense-mediated decay (NMD). Importantly, dysfunctional SBP2 is associated with endocrine disorders in humans. Here we describe the impact of induced Sbp2 deficiency in pancreatic ß-cells on selenoprotein transcript profiles in the pancreatic islets of C57BL/6J mice. Sex differences were noted in control mice, in which female islets showed 5 selenoproteins decreased and one increased versus male islets. Induced Sbp2 deficiency in pancreatic ß-cells altered expression of only 3 selenoprotein transcripts in male islets, whereas 14 transcripts were reduced in female islets. In all cases, decreased transcription was observed in genes known to be regulated by NMD. The differential impact of Sbp2 deletion on selenoprotein transcription between sexes suggests sex-specific hierarchical mechanisms of selenoprotein expression that may influence islet biology and consequentially metabolic disease risk.

Inherited defects of thyroid hormone metabolism.

Intracellular metabolism of thyroid hormone and availability of the active hormone, triiodothyronine is regulated by three selenoprotein iodothyronine deiodinases (Ds). While acquired changes in D activities are common, inherited defects in humans have not been identified. Selenium (Se) is an essential trace element required for the biosynthesis of selenoproteins, and selenocysteine insertion sequence (SECIS) binding protein 2 (SBP2) represents a key trans-acting factor for the cotranslational insertion of selenocysteine into selenoproteins. In 2005 we reported the first mutations in the SBP2 gene in two families in which the probands presented with transient growth retardation associated with abnormal thyroid function tests, low triiodothyronine (T3), high thyroxine (T4) and reverse T3, and slightly elevated thyrotropin. Affected children were either homozygous or compound heterozygous for SBP2 gene mutations and the relatively mild phenotype was due to partial SBP2 deficiency, affecting the expression of a subset of selenoproteins. In vivo studies of these subjects have explored the effects of Se and thyroid hormone supplementation. In vitro experiments have provided new insights into the effect of SBP2 mutations. A broader and more complex phenotype was brought to light by the subsequent identification of three new cases from different families with SBP2 gene mutations. These mutations caused a severe SBP2 deficiency resulting in reduced synthesis of most of the 25 known human selenoproteins. Here we summarize the clinical presentation of SBP2 mutations, their effect on SBP2 function and downstream consequences for selenoprotein synthesis and function.

Stanniocalcin 1 induction by thyroid hormone depends on thyroid hormone receptor ß and phosphatidylinositol 3-kinase activation.

CONTEXT: Thyroid hormone (TH) mediated changes in gene expression were thought to be primarily initiated by the nuclear TH receptor (TR) binding to a thyroid hormone response element in the promoter of target genes. A recently described extranuclear mechanism of TH action consists of the association of TH-liganded TRß with phosphatidylinositol 3-kinase (PI3K) in the cytosol and subsequent activation of the PI3K pathway. OBJECTIVE: The aim of this study was to examine the effect of TH, TRß and PI3K on stanniocalcin 1 (STC1) expression in human cells. DESIGN: We treated human skin fibroblasts with triiodothyronine (T3) in the absence or presence of the PI3K inhibitor LY294002, a dominant negative PI3K subunit, Δp85α, and the protein synthesis inhibitor cycloheximide (CHX). The role of the TRß was studied in cells from patients with resistance to thyroid hormone (RTH). STC-1 mRNA expression was measured by real-time PCR. RESULTS: We found an induction of STC1 by T3 in normal cells, but less in cells from subjects with RTH (2.7 ± 0.2 vs. 1.6 ± 0.04, P < 0.01). The effect of T3 was completely abrogated by blocking PI3K with LY294002 (3.9 ± 0.5 vs. 0.85 ± 0.5; P < 0.05) and greatly reduced after transfection of a dominant negative PI3K subunit, demonstrating dependency on the PI3K pathway. CONCLUSION: These results establish STC1 as a TH target gene in humans. Furthermore, we show that STC1 induction by TH depends on both TRß and PI3K activation.

A case of Resistance to Thyroid Hormone without mutation in the thyroid hormone receptor beta.

BACKGROUND: Resistance to Thyroid Hormone (RTH) is a condition caused by tissue hyposensitivity to the effects of circulating thyroid hormone, and may be misdiagnosed as hyperthyroidism. AIMS: We report the first case of RTH in an Irish patient highlighting the clinical features and the pathophysiological mechanism underlying the characteristic laboratory abnormalities found in the condition. METHODS: We describe an isolated case of RTH initially misdiagnosed as hyperthyroidism, and detail the investigations which ultimately led to the correct diagnosis. Genetic screening of the thyroid hormone receptor beta gene was performed. RESULTS: Thyroid function tests including T3 suppression test and TRH-stimulation test suggested a diagnosis of RTH. Genetic testing failed to demonstrate a mutation in the thyroid hormone receptor. CONCLUSION: RTH is a rare inherited condition that may be misdiagnosed as hyperthyroidism. The case we describe most likely results from a de novo mutation in an as yet undiscovered gene. RTH should be considered in patients with elevated thyroid hormone levels and normal TSH so that unnecessary and potentially harmful treatment can be avoided.

[The incidence of influenzal, para-influenzal and adenoviral antigens in keratoconjunctivitis patients during immunization with NIVGRIP vaccine]. / Incidence des antigènes grippal, paragrippal et adénoviral chez des sujets à kérato-conjonctivite durant l'immunisation avec du vaccin NIVGRIP.

Repeated intranasal administrations of NIVGRIP, influenza inactivated vaccine, to patients with chronic recurrent keratoconjunctivitis, led to a significant reduction of respiratory virus incidence, as revealed by the immunofluorescence test in the conjunctive epithelial cells. The effect is probably due to endogenous interferon stimulation by the vaccine, at the nasopharyngeal level.

[Simultaneous detection by immunofluorescence of several viral infections and Mycoplasma, Chlamydia and Rickettsia burneti infections localized at the level of the conjunctival, nasal and pharyngeal mucosae of patients with recurring chronic keratoconjunctivitis]. / Détection simultanée par l'immunofluorescence de quelques infections à virus, Mycoplasma, Chlamydia et Rickettsia burneti, localisées au niveau des muqueuses conjonctivale, nasale et pharyngienne, chez des malades atteints de kérato-conjonctivite chronique récidivante.

A study was conducted of the viral and inframicrobial populations present in the conjunctival, nasal and pharyngeal mucous membranes by immunofluorescence techniques, using a twelve hyperimmune serum kit, in 120 patients with chronic, relapsing keratoconjunctivitis. Qualitative and quantitative differences were noted in the antigen levels in the three investigated mucous membranes. The number of antigens in the conjunctival and nasal epithelial cells was higher than in the pharyngeal ones: 117 and 113 positive IF tests for the first two against 95 for the third. Incidence of each of the individual antigens was two or three times higher in the conjunctival and nasal mucous membranes, excepting, however, the parainfluenza viruses which were equally frequent in all the three mucous membranes.

[Detection of type 1 and 2 herpetic antigens by immunofluorescence in patients with chronic or recurrent keratoconjunctivitis receiving therapy based on etiology]. / Incidence des antigènes herpétiques des types 1 et 2 décelés en immunofluorescence chez des malades souffrant de kérato-conjonctivite chronique ou récidivante, soumis à une thérapeutique étiologique.

Immunofluorescence (IF) techniques were used to evaluate the therapeutical efficiency of moroxidine hydrochloride against herpes virus (HSV) induced keratoconjunctivitis. In 56 out of the 77 followed-up and treated patients, the IF reactions revealed the presence of both types 1 and 2 of herpes virus, while in 21 only type 1 was found. The treatment with moroxidine hydrochloride led to a reduction of 63% and 92%, respectively, of the incidence of herpes virus type 1 and 2 antigens in the conjunctival cells, coincident with the improvement of clinical symptoms or persistent recovery.