Porcelli, Tommaso (2018) Type 2 deiodinase polymorphism Thr92Ala: characterization on a biological model and clinical implications. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Type 2 deiodinase polymorphism Thr92Ala: characterization on a biological model and clinical implications
Creators:
CreatorsEmail
Porcelli, Tommasotommasoporcelli@gmail.com
Date: 10 December 2018
Number of Pages: 57
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Clinica e Chirurgia
Dottorato: Terapie avanzate biomediche e chirirgiche
Ciclo di dottorato: 31
Coordinatore del Corso di dottorato:
nomeemail
Di Minno, GiovanniUNSPECIFIED
Tutor:
nomeemail
Salvatore, DomenicoUNSPECIFIED
Date: 10 December 2018
Number of Pages: 57
Uncontrolled Keywords: thyroid, thyroid hormones, type 2 deiodinase, D2, hypothyroidism,metabolism
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/13 - Endocrinologia
Date Deposited: 08 Jan 2019 08:24
Last Modified: 26 Jun 2020 08:37
URI: http://www.fedoa.unina.it/id/eprint/12520

Abstract

The production rate of thyroid hormones (TH) by thyroid gland is regulated by the hypothalamus-hypophysis-thyroid axis in order to maintain a highly stable plasmatic hormone concentration. On the contrary, the intracellular concentration of TH, namely triiodothyronine (T3) and thyroxine (T4), is subjected to dramatic changes in response to tissue-specific metabolic requests. The peripheral metabolism of TH is finely regulated by the deiodinase family of selenoproteins. Type 1 and type 2 deiodinases (D1 and D2) mediate the activation of the pro-hormone T4 into the active form T3, while the type 3 deiodinase (D3) inactivates both T4 and T3. The 80% of T3 production derives from peripheral T4 to T3 deiodination. D2 represents the major source of T3 in humans, with a 700-fold greater catalytic efficiency compared to D1. No mutations in D2 have been reported yet, but over the last few years several single nucleotide polymorphisms (SNP) have been identified. Among these, the SNP Thr92Ala (rs225014) of DIO2 gene is founded to be present in the general population with a prevalence that ranges between 12.9 and 14.9%. Aim of this study is to assess the biochemical and clinical significance of the Thr92Ala DIO2 gene polymorphism. To this end, we investigated the effects of Thr92Ala mutation in two biological models of D2-dependent tissues, namely, muscle stem cells and pituitary thyrotrophs. We demonstrated that the T4 to T3 conversion mediated by D2-Ala is reduced compared to D2-WT, since the T4 action in cells expressing D2-Ala resulted significantly impaired. In addiction, we compared the presurgical with the postsurgical TH levels profile in 140 patients subjected to total thyroidectomy and on levothyroxine monotherapy, and analyzed the DIO2 gene status in a subgroup of 102/140 of patients. We found that mean postsurgical FT3 levels were significantly lower than before surgery in patients carrying genotype DIO2Ala/Ala-WT compared to wild-type patients. In conclusion, this study provides the first evidence that the SNP Thr92Ala reduces the D2 enzymatic activity, supporting a customized treatment of hypothyroidism in athyreotic patients who complain hypothyroidism-like symptoms with LT4-only replacement therapy.

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