Abstract
Background: The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). Objective: To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). Methods: We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Results: Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Conclusions: Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated.
Journal Section:
Translational Thyroidology / Original Paper
References
1.
Allan W, Herndon CN, Dudley FC: Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am J Ment Defic 1944;48:325-334.
2.
Friesema EC, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, Barrett TG, Mancilla EE, Svensson J, Kester MH, Kuiper GG, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestrap AP, Visser TJ: Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004;364:1435-1437.
[PubMed]
3.
Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S: A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004;74:168-175.
[PubMed]
4.
Trajkovic M, Visser TJ, Mittag J, Horn S, Lukas J, Darras VM, Raivich G, Bauer K, Heuer H: Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. J Clin Invest 2007;117:627-635.
[PubMed]
5.
Dumitrescu AM, Liao XH, Weiss RE, Millen K, Refetoff S: Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice. Endocrinology 2006;147:4036-4043.
[PubMed]
6.
Wirth EK, Sheu SY, Chiu-Ugalde J, Sapin R, Klein MO, Mossbrugger I, Quintanilla-Martinez L, Hrabě de Angelis M, Krude H, Riebel T, Rothe K, Köhrle J, Schmid KW, Schweizer U, Grüters A: Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy. Eur J Endocrinol 2011;165:555-561.
[PubMed]
7.
Di Cosmo C, Liao XH, Ye H, Ferrara AM, Weiss RE, Refetoff S, Dumitrescu AM: Mct8-deficient mice have increased energy expenditure and reduced fat mass that is abrogated by normalization of serum T3 levels. Endocrinology 2013;154:4885-4895.
[PubMed]
8.
Trajkovic-Arsic M, Visser TJ, Darras VM, Friesema EC, Schlott B, Mittag J, Bauer K, Heuer H: Consequences of monocarboxylate transporter 8 deficiency for renal transport and metabolism of thyroid hormones in mice. Endocrinology 2010;151:802-809.
[PubMed]
9.
Wirth EK, Roth S, Blechschmidt C, Hölter SM, Becker L, Racz I, Zimmer A, Klopstock T, Gailus-Durner V, Fuchs H, Wurst W, Naumann T, Bräuer A, Hrabě de Angelis M, Köhrle J, Grüters A, Schweizer U: Neuronal 3′,3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome. J Neurosci 2009;29:9439-9449.
[PubMed]
10.
Trajkovic-Arsic M, Müller J, Darras VM, Groba C, Lee S, Weih D, Bauer K, Visser TJ, Heuer H: Impact of monocarboxylate transporter-8 deficiency on the hypothalamus- pituitary-thyroid axis in mice. Endocrinology 2010;151:5053-5062.
[PubMed]
11.
Di Cosmo C, Liao XH, Dumitrescu AM, Philp NJ, Weiss RE, Refetoff S: Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion. J Clin Invest 2010;120:3377-3388.
[PubMed]
12.
Liao XH, Di Cosmo C, Dumitrescu AM, Hernandez A, Van Sande J, St Germain DL, Weiss RE, Galton VA, Refetoff S: Distinct roles of deiodinases on the phenotype of Mct8 defect: a comparison of eight different mouse genotypes. Endocrinology 2011;152:1180-1191.
[PubMed]
13.
Streckfuss F, Hamann I, Schomburg L, Michaelis M, Sapin R, Klein MO, Köhrle J, Schweizer U: Hepatic deiodinase activity is dispensable for the maintenance of normal circulating thyroid hormone levels in mice. Biochem Biophys Res Commun 2005;337:739-745.
[PubMed]
14.
Leonard JL, Rosenberg IN: Iodothyronine 5′-deiodinase from rat kidney: substrate specificity and the 5′-deiodination of reverse triiodothyronine. Endocrinology 1980;107:1376-1383.
[PubMed]
15.
Seeher S, Atassi T, Mahdi Y, Carlson BA, Braun D, Wirth EK, Klein MO, Reix N, Miniard AC, Schomburg L, Hatfield DL, Driscoll DM, Schweizer U: Secisbp2 is essential for embryonic development and enhances selenoprotein expression. Antioxid Redox Signal 2014;21:835-849.
[PubMed]
16.
Schweizer U, Streckfuss F, Pelt P, Carlson BA, Hatfield DL, Köhrle J, Schomburg L: Hepatically derived selenoprotein P is a key factor for kidney but not for brain selenium supply. Biochem J 2005;386:221-226.
[PubMed]
17.
Sengupta A, Carlson BA, Weaver JA, Novoselov SV, Fomenko DE, Gladyshev VN, Hatfield DL: A functional link between housekeeping selenoproteins and phase II enzymes. Biochem J 2008;413:151-161.
[PubMed]
18.
Schneider MJ, Fiering SN, Thai B, Wu SY, St Germain E, Parlow AF, St Germain DL, Galton VA: Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice. Endocrinology 2006;147:580-589.
[PubMed]
© 2015 European Thyroid Association Published by S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2015
You do not currently have access to this content.
