348 research outputs found
Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA-Binding Region: In Vitro Studies Reveal Different Pathogenic Mechanisms
No full textBackground: Mutations in PAX8, a transcription factor gene, cause thyroid dysgenesis (TD). The extreme variability of the thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations. Methods: Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)- and the thyroperoxidase (TPO)-promoters. Results: S54R had an impaired binding to DNA and a negligible activity on the TG- and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it also exhibited dramatically impaired activation of the TG- and TPO-promoters. However, R133Q has no dominant negative effect on the WT protein in vitro. Thus, the underlying molecular mechanism by which the function of R133Q is impaired remains to be elucidated. Conclusions: We identified and functionally characterized two novel mutations of the PAX8 gene that lead to TD by distinct mechanisms. A structural defect of the mutant R133Q leading to a reduced capability for induced fit upon DNA interaction might explain the disparity between its apparently normal binding to DNA, but lack of promoter activation
The use of mice deficient in MCT8 to identify a mechanism regulating thyroid hormone secretion
No full textThe mechanism of thyroid hormone (TH) secretion from the thyroid gland into the bloodstream is still unknown. The aim of my thesis has been to investigate the role of monocarboxylate transporter 8 (MCT8) in this process. To accomplish the goal, we used the Mct8 deficient mice (Mct8KO), generated by homologous recombination. MCT8 is a specific transporter of TH across the cell membrane, active in both uptake and efflux. Mutations of MCT8 gene cause in human severe psychomotor retardation and thyroid function test abnormalities. The Mct8KO mice faithfully replicate the endocrine aberrances observed in humans, including a low concentration of serum thyroxine (T4). This latter finding cannot be fully explained by increased deiodination.
Here, we have shown that Mct8 is localized at the basolateral membrane of thyrocytes and that the serum TH concentration is reduced in Mct8KO mice early after being taken off a treatment that almost completely depleted the thyroid gland of TH. Furthermore, thyroid glands in Mct8KO mice contained 2.3-fold and 1.5-fold more non thyroglobulin associated T4 and triiodothyronine (T3), respectively, than did those in wild-type (Wt) mice. This was independent of deiodination, as comparable increases were also found in Mct8KO mice which lacked the types 1 and 2 deiodinases. In addition, depletion of thyroidal TH content was slower during iodine deficiency. After administration of 125I, the rate of both its secretion from the thyroid gland and its appearance in the serum as trichloroacetic acid-precipitable radioactivity were greatly reduced in Mct8KO mice. Similarly, the secretion of T4 induced by injection of thyrotropin was reduced in Mct8KO in which endogenous TSH and T4 were suppressed by administration of T3.
This study is the first to demonstrate that Mct8 is involved in the secretion of TH from the thyroid gland. The defect in the efflux contributes, in part, to the low serum T4 level observed in Mct8 deficiency
A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene
No full textThyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613–amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter
Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia
No full textHere we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene-induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers γH2AX and pChk2 T68, and induction of p53 and p19ARF. After 5 months, about half of thyroid lesions escaped OIS and formed tumors that remained dependent on RET/PTC3 expression. This progression was accompanied by activation of AKT-FOXO1/3a pathway and increased serum TSH levels
Thyroiditis and Thyroid Function: Clinical, Morphological, and Physiopathological Studies
No full textResistance to thyroid hormone: one of several defects causing reduced sensitivity to thyroid hormone
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