The Experts below are selected from a list of 3543 Experts worldwide ranked by ideXlab platform

Theo J. Visser - One of the best experts on this subject based on the ideXlab platform.

  • Thyroid hormone availability in the human fetal brain: novel entry pathways and role of radial glia
    Brain Structure and Function, 2019
    Co-Authors: Daniela López-espíndola, Theo J. Visser, Juan Bernal, Ángel García-aldea, Inés Gómez De La Riva, Ana Margarita Rodríguez-garcía, Domenico Salvatore, Ana Guadaño-ferraz
    Abstract:

    Thyroid hormones (TH) are crucial for brain development; their deficiency during neurodevelopment impairs neural cell differentiation and causes irreversible neurological alterations. Understanding TH action, and in particular the mechanisms regulating TH availability in the prenatal human brain is essential to design therapeutic strategies for neurological diseases due to impaired TH signaling during neurodevelopment. We aimed at the identification of cells involved in the regulation of TH availability in the human brain at fetal stages. To this end, we studied the distribution of the TH Transporters Monocarboxylate Transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1), as well as the TH-metabolizing enzymes types 2 and 3 deiodinases (DIO2 and DIO3). Paraffin-embedded human brain sections obtained from necropsies of thirteen fetuses from 14 to 38 gestational weeks were analyzed by immunohistochemistry and in situ hybridization. We found these proteins localized along radial glial cells, in brain barriers, in Cajal-Retzius cells, in migrating fibers of the brainstem and in some neurons and glial cells with particular and complex spatiotemporal patterns. Our findings point to an important role of radial glia in controlling TH delivery and metabolism and suggest two additional novel pathways for TH availability in the prenatal human brain: the outer, and the inner cerebrospinal fluid–brain barriers. Based on our data we propose a model of TH availability for neural cells in the human prenatal brain in which several cell types have the ability to autonomously control the required TH content.

  • effects of chemical chaperones on thyroid hormone transport by mct8 mutants in patient derived fibroblasts
    Endocrinology, 2018
    Co-Authors: Stefan Groeneweg, Theo J. Visser, Amanda Van Den Berge, Marcel E Meima, Robin P Peeters, Edward W Visser
    Abstract:

    Mutations in the thyroid hormone (TH) Transporter Monocarboxylate Transporter 8 (MCT8) result in severe intellectual and motor disability. At present, no effective therapy is available to restore TH signaling in MCT8-dependent tissues. Recent in vitro studies in stable overexpression cell models suggested that the function of certain mutant MCT8 proteins, specifically those that affect protein stability and intracellular trafficking (e.g., p.F501del), could be partially recovered by chemical chaperones. However, the effects of chaperones have not been demonstrated in other commonly used models for MCT8 deficiency, including transient overexpression models and patient-derived fibroblasts. Here, we demonstrate that the chemical chaperone 4-phenylbutyric acid (PBA) similarly potentiates the T3 transport function of wild-type and p.F501del mutant MCT8 in transiently transfected COS-1 cells by increasing MCT8 messenger RNA, total protein, and cell surface expression levels. Although PBA also increased the cell surface expression levels of the p.R445L mutant, no functional improvement was observed, which is in line with the proposed important role of Arg445 in substrate translocation. In contrast, PBA showed only minimal effects in ex vivo studies using control or p.F501del patient-derived fibroblasts. Moreover, the MCT8-specific inhibitor silychristin did not change these minimal effects, suggesting that the underlying mechanism is unrelated to the rescue of functional MCT8. Together, these findings indicate that the potency of chaperones to rescue mutant MCT8 function strongly depends on the cellular model and stress the need for further preclinical studies before clinically available chaperones should be considered as a treatment option in patients with MCT8 deficiency.

  • thyroid hormone Transporters and resistance
    Endocrine development, 2013
    Co-Authors: Theo J. Visser
    Abstract:

    Cellular entry is an important step preceding intracellular metabolism and action of thyroid hormone (TH). Transport of TH across the plasma membrane does not take place by simple diffusion but requires Transporter proteins. One of the most effective and specific TH Transporters identified to date is Monocarboxylate Transporter 8 (MCT8), the gene of which is located on the X chromosome. Although MCT8 is expressed in many tissues, its function appears to be most critical in the brain. Hemizygous MCT8 mutations in males cause severe psychomotor retardation, known as the Allan-Herndon-Dudley syndrome (AHDS), and abnormal serum TH levels. AHDS thus represents a type of TH resistance caused by a defect in cellular TH transport.

  • Monocarboxylate Transporter 8 modulates the viability and invasive capacity of human placental cells and fetoplacental growth in mice
    PLOS ONE, 2013
    Co-Authors: Elisavet Vasilopoulou, H Heuer, Theo J. Visser, Marija Trajkovicarsic, Veerle Darras, Christopher Mccabe, Laurence Loubiere, Gendie E Lash, Guy St J Whitley, J A Franklyn
    Abstract:

    Monocarboxylate Transporter 8 (MCT8) is a well-established thyroid hormone (TH) Transporter. In humans, MCT8 mutations result in changes in circulating TH concentrations and X-linked severe global neurodevelopmental delay. MCT8 is expressed in the human placenta throughout gestation, with increased expression in trophoblast cells from growth-restricted pregnancies. We postulate that MCT8 plays an important role in placental development and transplacental TH transport. We investigated the effect of altering MCT8 expression in human trophoblast in vitro and in a Mct8 knockout mouse model. Silencing of endogenous MCT8 reduced T3 uptake into human extravillous trophoblast-like cells (SGHPL-4; 40%, P<0.05) and primary cytotrophoblast (15%, P<0.05). MCT8 over-expression transiently increased T3 uptake (SGHPL-4∶30%, P<0.05; cytotrophoblast: 15%, P<0.05). Silencing MCT8 did not significantly affect SGHPL-4 invasion, but with MCT8 over-expression T3 treatment promoted invasion compared with no T3 (3.3-fold; P<0.05). Furthermore, MCT8 silencing increased cytotrophoblast viability (∼20%, P<0.05) and MCT8 over-expression reduced cytotrophoblast viability independently of T3 (∼20%, P<0.05). In vivo, Mct8 knockout reduced fetal:placental weight ratios compared with wild-type controls at gestational day 18 (25%, P<0.05) but absolute fetal and placental weights were not significantly different. The volume fraction of the labyrinthine zone of the placenta, which facilitates maternal-fetal exchange, was reduced in Mct8 knockout placentae (10%, P<0.05). However, there was no effect on mouse placental cell proliferation in vivo. We conclude that MCT8 makes a significant contribution to T3 uptake into human trophoblast cells and has a role in modulating human trophoblast cell invasion and viability. In mice, Mct8 knockout has subtle effects upon fetoplacental growth and does not significantly affect placental cell viability probably due to compensatory mechanisms in vivo.

  • identification functional analysis prevalence and treatment of Monocarboxylate Transporter 8 mct8 mutations in a cohort of adult patients with mental retardation
    Clinical Endocrinology, 2013
    Co-Authors: Edward W Visser, Paul Vrijmoeth, Frank E Visser, W F M Arts, Hans Van Toor, Theo J. Visser
    Abstract:

    SummaryObjective Monocarboxylate Transporter 8 (MCT8) is an essential thyroid hormone (TH) Transporter as humans with MCT8 mutations have severe neurological and endocrine abnormalities. The objectives are (i) to identify novel MCT8 mutations and (ii) to assess their functional relevance; (iii) to describe the effects of block-and-replace treatment in an MCT8 patient. Design The TOP-R study is a cross-sectional nation-wide multicentre study. Patients Subjects with unexplained mental retardation (MR) were screened for MCT8 mutations. Results We identified three mutations: p.F501del (previously described), p.L492P and p.T162T. The F501del and L492P mutants, but not the T162T mutant, showed diminished T3, T4 and rT3 transport in transfected cells. TH transport in T162T fibroblasts was also not affected. One patient was treated with block-and-replace therapy to normalize serum TH levels. The results indicated a slow onset of the decrease in serum T4 and T3 by successive treatment with methimazole and PTU, and eventually their complete normalization by administration of LT4 with PTU but not with methimazole. The frequency of MCT8 mutations in males with X-linked MR approximately 3·9%. Conclusions We identified several MCT8 mutations in a cohort of subjects with unexplained MR. We demonstrated the pathogenicity of two missense mutations. The synonymous variant did not affect TH transport. Block-and-replace therapy of one patient reversed the TH abnormalities. Our data suggest a decreased TH secretion rate and an increased T4 to T3 conversion by the type I deiodinase in patients with MCT8 mutations. Our study indicates that MCT8 mutations are a relatively frequent cause of X-linked MR.

Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.

  • prenatal treatment of thyroid hormone cell membrane transport defect caused by mct8 gene mutation
    Thyroid, 2020
    Co-Authors: Samuel Refetoff, Theodora Pappa, Meredith K Williams, Gisele M Matheus, Xiao Hui Liao, Karen Hansen, Lindsey Nicol, Melinda Pierce, Peter A Blasco, Mandie Wiebers Jensen
    Abstract:

    Background: Mutations of the thyroid hormone (TH)-specific cell membrane Transporter, Monocarboxylate Transporter 8 (MCT8), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum triiodothyronine (T3) corrects hypermetabolism, but has no effect on the psychoneuromotor deficits. Studies of brain from a 30-week-old MCT8-deficient embryo indicated that brain abnormalities were already present during fetal life. Methods: A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 μg intra-amniotic instillation of levothyroxine (LT4) from 18 weeks of gestation until birth at 35 weeks. Thyroxine (T4), T3, and thyrotropin (TSH) were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with LT4 and propylthiouracil. Follow-up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation, both compared with the untreated brother. Results: During intrauterine life, T4 and T3 in the amniotic fluid were maintained above threefold to twofold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth, the infant serum T4 was 14.5 μg/dL and TSH 8 mU/L, respectively. MRI at six months of age showed near-normal brain myelination compared with much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language and problem-solving, and gross motor and fine motor function ranged from 12 to 25 at 31 months in the treated boy and from 1 to 7 at 58 months in the untreated brother. Conclusions: This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in the fetus when given to the mother may further rescue the phenotype.

  • Intranasal delivery of Thyroid hormones in MCT8 deficiency.
    'Public Library of Science (PLoS)', 2020
    Co-Authors: Carmen Grijota-martínez, Samuel Refetoff, Soledad Bárez-lópez, Eva Ausó, William H Frey, Ana Guadaño-ferraz
    Abstract:

    Loss of function mutations in the gene encoding the thyroid hormone Transporter Monocarboxylate Transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport

  • adeno associated virus 9 based gene therapy delivers a functional Monocarboxylate Transporter 8 improving thyroid hormone availability to the brain of mct8 deficient mice
    Thyroid, 2016
    Co-Authors: Hideyuki Iwayama, Alexandra M Dumitrescu, Xiao Hui Liao, Roy E Weiss, Soledad Barezlopez, Ana Guadanoferraz, Lyndsey Braun, Brian K Kaspar, Samuel Refetoff
    Abstract:

    BACKGROUND MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. This proof-of-concept study examined whether transfer of human MCT8 (hMCT8) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice (Mct8KO). METHODS AAV9 vectors delivering long and/or short hMCT8 protein isoforms or an empty vector were injected intravenously (IV) and/or intracerebroventricularly (ICV) into postnatal day 1 Mct8KO and wild type (Wt) mice. Triiodothyronine (T3) was given daily for four days before postnatal day 28, at which time brains were collected after perfusion to assess increase in T3 content and effect on the T3-responsive transcription factor, Hairless. RESULTS Increased pup mortality was observed after IV injection of the AAV9-long hMCT8 isoform, but not after injection of AAV9-short hMCT8 isoform. Compared to IV, ICV delivery produced more hMCT8 mRNA and protein relative to the viral dose, which was present in various brain regions and localized to the cell membranes. Despite production of abundant hMCT8 mRNA and protein with ICV delivery, only IV delivered AAV9-hMCT8 targeted the choroid plexus and significantly increased brain T3 content and expression of Hairless. CONCLUSIONS These results indicate that MCT8 delivery to brain barriers by IV but not ICV injection is crucial for its proper function. MCT8 has no constitutive activity but acts through an increase in T3 entering the brain tissue. Increasing MCT8 expression in brain cell membranes, including neurons, is insufficient to produce an effect without an increase in brain T3 content. The correct hMCT8 isoform along with an optimized delivery method are critical for an effective gene therapy to provide functional MCT8 in the brain of patients with MCT8 mutations.

  • desensitization and incomplete recovery of hepatic target genes after chronic thyroid hormone treatment and withdrawal in male adult mice
    Endocrinology, 2016
    Co-Authors: Kenji Ohba, Xiao Hui Liao, Melvin Kheeshing Leow, Brijesh K Singh, Rohit A Sinha, Ronny Lesmana, Sujoy Ghosh, Samuel Refetoff
    Abstract:

    Clinical symptoms may vary and not necessarily reflect serum thyroid hormone (TH) levels during acute and chronic hyperthyroidism as well as recovery from hyperthyroidism. We thus examined changes in hepatic gene expression and serum TH/TSH levels in adult male mice treated either with a single T3 (20 μg per 100 g body weight) injection (acute T3) or daily injections for 14 days (chronic T3) followed by 10 days of withdrawal. Gene expression arrays from livers harvested at these time points showed that among positively-regulated target genes, 320 were stimulated acutely and 429 chronically by T3. Surprisingly, only 69 of 680 genes (10.1%) were induced during both periods, suggesting desensitization of the majority of acutely stimulated target genes. About 90% of positively regulated target genes returned to baseline expression levels after 10 days of withdrawal; however, 67 of 680 (9.9%) did not return to baseline despite normalization of serum TH/TSH levels. Similar findings also were observed for negatively regulated target genes. Chromatin immunoprecipitation analysis of representative positively regulated target genes suggested that acetylation of H3K9/K14 was associated with acute stimulation, whereas trimethylation of H3K4 was associated with chronic stimulation. In an in vivo model of chronic intrahepatic hyperthyroidism since birth, adult male Monocarboxylate Transporter-8 knockout mice also demonstrated desensitization of most acutely stimulated target genes that were examined. In summary, we have identified transcriptional desensitization and incomplete recovery of gene expression during chronic hyperthyroidism and recovery. Our findings may be a potential reason for discordance between clinical symptoms and serum TH levels observed in these conditions.

  • the thyroid hormone analog ditpa ameliorates metabolic parameters of male mice with mct8 deficiency
    Endocrinology, 2015
    Co-Authors: Alfonso Massimiliano Ferrara, Xiao Hui Liao, Alexandra M Dumitrescu, Roy E Weiss, Samuel Refetoff
    Abstract:

    Mutations in the gene encoding the thyroid hormone (TH) Transporter, Monocarboxylate Transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

Ulrich Schweizer - One of the best experts on this subject based on the ideXlab platform.

  • Thyroid Hormone Transport and Transporters.
    Vitamins and Hormones Series, 2017
    Co-Authors: Doreen Braun, Ulrich Schweizer
    Abstract:

    Abstract Thyroid hormones orchestrate developmental processes and are among the most important regulators of energy metabolism. Thyroid hormone actions are mostly, but not exclusively, mediated by nuclear hormone receptors. As amino acid derivatives, thyroid hormones need plasma membrane Transporters in order to reach their nuclear receptors. Several Transporters from different gene families mediate thyroid hormone uptake into cells. Monocarboxylate Transporter 8 is a specific thyroid hormone Transporter found mutated in patients with severe psychomotor retardation and strangely abnormal thyroid hormone constellations. These patients display a syndrome in which some organs are exposed to increased thyroid hormone signaling, while other organs are lacking thyroid hormone signaling due to complete lack of thyroid hormone uptake. Investigations in many organ systems using mouse models of thyroid hormone transmembrane Transporter deficiency have helped complete our picture of thyroid hormone metabolism and action in the body during development and under different physiological conditions. Incorporating the concept of thyroid hormone transmembrane transport has helped understand previously enigmatic drug interactions and may explain how the hormonal set points in the hypothalamus–pituitary–thyroid axis are established.

  • the chemical chaperone phenylbutyrate rescues mct8 mutations associated with milder phenotypes in patients with allan herndon dudley syndrome
    Endocrinology, 2016
    Co-Authors: Doreen Braun, Ulrich Schweizer
    Abstract:

    Mutations in the thyroid hormone Transporter Monocarboxylate Transporter 8 (MCT8) prevent appropriate entry of thyroid hormones into brain cells during development and cause severe mental retardation in affected patients. The current treatment options are thyromimetic compounds that enter the brain independently of MCT8. Some MCT8-deficient patients (e.g., those carrying MCT8delF501) will not be as severely affected as most others. We have shown that the MCT8delF501 protein has decreased protein stability but important residual function once it reaches the plasma membrane. We were able to rescue protein expression and the function of MCT8delF501 in a Madin-Darby canine kidney cell model by application of the chemical chaperone sodium phenylbutyrate (NaPB), a drug that has been used to treat patients with cystic fibrosis and urea cycle defects for extended periods of time. In the present study, we have extended our previous study and report on the NaPB-dependent rescue of a series of other pathogenic MCT8 mutants associated with milder patient phenotypes. We show that NaPB can functionally rescue the expression and activities of Ser194Phe, Ser290Phe, Leu434Trp, Arg445Cys, Leu492Pro, and Leu568Pro mutations in MCT8 in a dose-dependent manner. The soy isoflavone genistein, a dietary supplement, which was effective in MCT8delF501, was also effective in increasing the expression and transport of these MCT8 mutants; however, the effect size differed among mutants. Kinetic analyses revealed that the Michaelis constants of the mutants toward the primary substrate 3,3',5-triiodothyronine were not much different from the wild-type value, suggesting that these mutants are not impaired in their interaction with substrate but rather destabilized by the mutation and degraded.

  • transport of thyroid hormone in brain
    Frontiers in Endocrinology, 2014
    Co-Authors: Eva K. Wirth, Ulrich Schweizer, Josef Kohrle
    Abstract:

    Thyroid hormone (TH) transport into the brain is not only pivotal for development and differentiation, but also for maintenance and regulation of adult central nervous system (CNS) function. In this review, we highlight some key factors and structures regulating thyroid hormone uptake and distribution. Serum TH binding proteins play a major role for the availability of TH since only free hormone concentrations may dictate cellular uptake. One of these proteins, transthyretin is also present in the cerebrospinal fluid (CSF) after being secreted by the choroid plexus. Entry routes into the brain like the blood-brain-barrier (BBB) and the blood-CSF-barrier will be explicated regarding fetal and adult status. Recently identified TH transmembrane Transporters (THTT) like Monocarboxylate Transporter 8 (Mct8) play a major role in uptake of TH across the BBB but as well in transport between cells like astrocytes and neurons within the brain. Species differences in Transporter expression will be presented and interference of TH transport by endogenous and exogenous compounds including endocrine disruptors and drugs will be discussed.

  • tyrosine kinase inhibitors noncompetitively inhibit mct8 mediated iodothyronine transport
    The Journal of Clinical Endocrinology and Metabolism, 2012
    Co-Authors: Doreen Braun, Josef Kohrle, Theo D Kim, Philipp Le Coutre, Jerome M Hershman, Ulrich Schweizer
    Abstract:

    Context: Tyrosine kinase inhibitors (TKI) are used for the treatment of various cancers. Case reports and clinical trials have reported abnormal thyroid function tests (TFT) after treatment with sunitinib, imatinib, sorafenib, dasatinib, and nilotinib. An increased requirement for levothyroxine was reported in thyroidectomized patients during TKI treatment. Objective: We hypothesized that abnormal TFT are compatible with inhibition of thyroid hormone (TH) Transporters and subsequently reduced pituitary-TH feedback. Monocarboxylate Transporter 8 (MCT8) is a TH transmembrane Transporter in brain, pituitary, and other organs. MCT8 mutation leads to abnormal TFT in patients and respective mouse models. We tested whether TKI are able to inhibit MCT8-mediated TH uptake into cells. Design: Madin-Darby-canine kidney (MDCK1) cells stably expressing human MCT8 were exposed in vitro to TKI at increasing concentrations, and MCT8-mediated [125I]T3 uptake and efflux were measured. The mode of inhibition was determined....

  • aminoaciduria but normal thyroid hormone levels and signalling in mice lacking the amino acid and thyroid hormone Transporter slc7a8
    Biochemical Journal, 2011
    Co-Authors: Doreen Braun, Eva K. Wirth, Franziska Wohlgemuth, Nathalie Reix, M Klein, Annette Gruters, Josef Kohrle, Ulrich Schweizer
    Abstract:

    LAT2 (system L amino acid Transporter 2) is composed of the subunits Slc7a8 /Lat2 and Slc3a2 /4F2hc. This Transporter is highly expressed along the basolateral membranes of absorptive epithelia in kidney and small intestine, but is also abundant in the brain. Lat2 is an energy-independent exchanger of neutral amino acids, and was shown to transport thyroid hormones. We report in the present paper that targeted inactivation of Slc7a8 leads to increased urinary loss of small neutral amino acids. Development and growth of Slc7a8 −/− mice appears normal, suggesting functional compensation of neutral amino acid transport by alternative Transporters in kidney, intestine and placenta. Movement co-ordination is slightly impaired in mutant mice, although cerebellar development and structure remained inconspicuous. Circulating thyroid hormones, thyrotropin and thyroid hormone-responsive genes remained unchanged in Slc7a8 −/− mice, possibly because of functional compensation by the thyroid hormone Transporter Mct8 (Monocarboxylate Transporter 8), which is co-expressed in many cell types. The reason for the mild neurological phenotype remains unresolved.

Edith C. H. Friesema - One of the best experts on this subject based on the ideXlab platform.

  • relevance of different cellular models in determining the effects of mutations on slc16a2 mct8 thyroid hormone Transporter function and genotype phenotype correlation
    Human Mutation, 2013
    Co-Authors: Edith C. H. Friesema, Yline Capri, Simone Kersseboom, Renaud Touraine, Aurelie Monnier, Eleonore Eymardpierre, Vincent Des Portes, Giusseppe De Michele, Angela F Brady
    Abstract:

    SLC 16A2, the gene for the second member of the solute carrier family 16 (monocarboxylic acid Transporter), located on chromosome Xq13.2, encodes a very efficient thyroid hormone Transporter: Monocarboxylate Transporter 8, MCT8. Its loss of function is responsible in males for a continuum of psychomotor retardation ranging from severe (no motor acquisition, no speech) to mild (ability to walk with help and a few words of speech). Triiodothyronine uptake measurement in transfected cells and, more recently, patient fibroblasts, has been described to study the functional consequences of MCT8 mutations. Here, we describe three novel MCT8 mutations, including one missense variation not clearly predicted to be damaging but found in a severely affected patient. Functional studies in fibroblasts and JEG3 cells demonstrate the usefulness of both cellular models in validating the deleterious effects of a new MCT8 mutation if there is still a doubt as to its pathogenicity. Moreover, the screening of fibroblasts from a large number of patient fibroblasts and of transfected mutations has allowed us to demonstrate that JEG3 transfected cells are more relevant than fibroblasts in revealing a genotype-phenotype correlation.

  • consequences of Monocarboxylate Transporter 8 deficiency for renal transport and metabolism of thyroid hormones in mice
    Endocrinology, 2010
    Co-Authors: Marija Trajkovicarsic, Edith C. H. Friesema, Theo J. Visser, Karl Bauer, Veerle Darras, Bernhard Schlott, Jens Mittag, H Heuer
    Abstract:

    Patients carrying inactivating mutations in the gene encoding the thyroid hormone transporting Monocarboxylate Transporter (MCT)-8 suffer from a severe form of psychomotor retardation and exhibit abnormal serum thyroid hormone levels. The thyroidal phenotype characterized by high-serum T3 and low-serum T4 levels is also found in mice mutants deficient in MCT8 although the cause of these abnormalities is still unknown. Here we describe the consequences of MCT8 deficiency for renal thyroid hormone transport, metabolism, and function by studying MCT8 null mice and wild-type littermates. Whereas serum and urinary parameters do not indicate a strongly altered renal function, a pronounced induction of iodothyronine deiodinase type 1 expression together with increased renal T3 and T4 content point to a general hyperthyroid state of the kidneys in the absence of MCT8. Surprisingly, accumulation of peripherally injected T4 and T3 into the kidneys was found to be enhanced in the absence of MCT8, indicating that MCT...

  • functional analysis of Monocarboxylate Transporter 8 mutations identified in patients with x linked psychomotor retardation and elevated serum triiodothyronine
    The Journal of Clinical Endocrinology and Metabolism, 2007
    Co-Authors: Jurgen Jansen, Edith C. H. Friesema, Monique H A Kester, Annette Gruters, Maarten Reeser, Timothy Barrett, Edna E Mancilla, Johan Svensson, Carmelina Milici, Jeanlouis Wemeau
    Abstract:

    Context: T-3 action in neurons is essential for brain development. Recent evidence indicates that Monocarboxylate Transporter 8 (MCT8) is important for neuronal T-3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T-3 levels. Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T-3. Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T-3 uptake, 2) T-3 metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T-3 levels in these patients are caused by inactivation of the MCT8 Transporter, preventing action and metabolism of T-3 in central neurons.

  • thyroid hormone transport by the human Monocarboxylate Transporter 8 and its rate limiting role in intracellular metabolism
    Molecular Endocrinology, 2006
    Co-Authors: Edith C. H. Friesema, Theo J. Visser, Jurgen Jansen, George G J M Kuiper, Monique H A Kester
    Abstract:

    Cellular entry of thyroid hormone is mediated by plasma membrane Transporters. We have identified rat Monocarboxylate Transporter 8 (MCT8) as an active and specific thyroid hormone Transporter. The MCT8 gene is located on the X-chromosome. The physiological relevance of MCT8 has been demonstrated by the identification of hemizygous mutations in this gene in males with severe psychomotor retardation and elevated serum T(3) levels. We have characterized human (h) MCT8 by analysis of iodothyronine uptake and metabolism in cell lines transiently transfected with hMCT8 cDNA alone or together with cDNA coding for iodothyronine deiodinase D1, D2, or D3. MCT8 mRNA was detected by RT-PCR in a number of human cell lines as well as in COS1 cells but was low to undetectable in other cell lines, including JEG3 cells. MCT8 protein was not detected in nontransfected cell lines tested by immunoblotting using a polyclonal C-terminal hMCT8 antibody but was detectable in transfected cells at the expected size (61 kDa). Transfection of COS1 and JEG3 cells with hMCT8 cDNA resulted in 2- to 3-fold increases in uptake of T(3) and T(4) but little or no increase in rT(3) or 3,3'-diiodothyronine (3,3'-T(2)) uptake. MCT8 expression produced large increases in T(4) metabolism by cotransfected D2 or D3, T(3) metabolism by D3, rT(3) metabolism by D1 or D2, and 3,3'-T(2) metabolism by D3. Affinity labeling of hMCT8 protein was observed after incubation of intact transfected cells with N-bromoacetyl-[(125)I]T(3). hMCT8 also facilitated affinity labeling of cotransfected D1 by bromoacetyl-T(3). Our findings indicate that hMCT8 mediates plasma membrane transport of iodothyronines, thus increasing their intracellular availability.

  • mechanisms of disease psychomotor retardation and high t3 levels caused by mutations in Monocarboxylate Transporter 8
    Nature Clinical Practice Endocrinology & Metabolism, 2006
    Co-Authors: Edith C. H. Friesema, H Heuer, Jurgen Jansen, Karl Bauer, Marija Trajkovic, Theo J. Visser
    Abstract:

    Thyroid hormone transport across the plasma membrane is essential for hormone functions. As detailed here, novel mutations in Monocarboxylate Transporter 8 reveal important roles in thyroid hormone access to the brain and might explain the pathogenesis of Allan–Herndon–Dudley syndrome, which is now known to feature thyroid hormone resistance. The actions and the metabolism of thyroid hormone are intracellular events that require the transport of iodothyronines across the plasma membrane. It is increasingly clear that this process does not occur by simple diffusion, but is facilitated by transport proteins. Only recently have iodothyronine Transporters been identified at the molecular level, of which organic anion transporting polypeptide 1C1 and Monocarboxylate Transporter 8 (MCT8) deserve special mention, because of their high activity and specificity for iodothyronines. Organic anion transporting polypeptide 1C1 is almost exclusively expressed in brain capillaries, and may be crucial for the transport of the prohormone T4 across the blood–brain barrier. MCT8 is also expressed in the brain—in particular, in neurons—but also in other tissues. MCT8 seems to be especially important for the uptake of active hormone T3 into neurons, which is essential for optimal brain development. T3 is produced from T4 by type 2 deiodinase in neighboring astrocytes. Neurons express type 3 deiodinase, the enzyme that terminates T3 activity. The SLC16A2 (formerly MCT8) gene is located on chromosome Xq13.2 and has recently been associated with a syndrome combining severe, X-linked, psychomotor retardation and high serum T3 levels. In over 20 families, where affected males have developed this syndrome, several mutations in MCT8 have been identified. The disease mechanism is thought to involve a defect in the neuronal entry of T3 and, therefore, in the action and metabolism of T3 in these cells. This defect results in impaired neurological development and a decrease in T3 clearance.

Alexandra M Dumitrescu - One of the best experts on this subject based on the ideXlab platform.

  • adeno associated virus 9 based gene therapy delivers a functional Monocarboxylate Transporter 8 improving thyroid hormone availability to the brain of mct8 deficient mice
    Thyroid, 2016
    Co-Authors: Hideyuki Iwayama, Alexandra M Dumitrescu, Xiao Hui Liao, Roy E Weiss, Soledad Barezlopez, Ana Guadanoferraz, Lyndsey Braun, Brian K Kaspar, Samuel Refetoff
    Abstract:

    BACKGROUND MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. This proof-of-concept study examined whether transfer of human MCT8 (hMCT8) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice (Mct8KO). METHODS AAV9 vectors delivering long and/or short hMCT8 protein isoforms or an empty vector were injected intravenously (IV) and/or intracerebroventricularly (ICV) into postnatal day 1 Mct8KO and wild type (Wt) mice. Triiodothyronine (T3) was given daily for four days before postnatal day 28, at which time brains were collected after perfusion to assess increase in T3 content and effect on the T3-responsive transcription factor, Hairless. RESULTS Increased pup mortality was observed after IV injection of the AAV9-long hMCT8 isoform, but not after injection of AAV9-short hMCT8 isoform. Compared to IV, ICV delivery produced more hMCT8 mRNA and protein relative to the viral dose, which was present in various brain regions and localized to the cell membranes. Despite production of abundant hMCT8 mRNA and protein with ICV delivery, only IV delivered AAV9-hMCT8 targeted the choroid plexus and significantly increased brain T3 content and expression of Hairless. CONCLUSIONS These results indicate that MCT8 delivery to brain barriers by IV but not ICV injection is crucial for its proper function. MCT8 has no constitutive activity but acts through an increase in T3 entering the brain tissue. Increasing MCT8 expression in brain cell membranes, including neurons, is insufficient to produce an effect without an increase in brain T3 content. The correct hMCT8 isoform along with an optimized delivery method are critical for an effective gene therapy to provide functional MCT8 in the brain of patients with MCT8 mutations.

  • the thyroid hormone analog ditpa ameliorates metabolic parameters of male mice with mct8 deficiency
    Endocrinology, 2015
    Co-Authors: Alfonso Massimiliano Ferrara, Xiao Hui Liao, Alexandra M Dumitrescu, Roy E Weiss, Samuel Refetoff
    Abstract:

    Mutations in the gene encoding the thyroid hormone (TH) Transporter, Monocarboxylate Transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

  • placenta passage of the thyroid hormone analog ditpa to male wild type and mct8 deficient mice
    Endocrinology, 2014
    Co-Authors: Alfonso Massimiliano Ferrara, Juan Bernal, Alexandra M Dumitrescu, Xiao Hui Liao, Roy E Weiss, Pilar Gilibanez, Samuel Refetoff
    Abstract:

    Monocarboxylate Transporter 8 (MCT8) deficiency causes severe X-linked intellectual and neuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analog diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8-deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8-deficient embryos to determine whether DITPA, when given prenatally, crosses the placenta and affects the serum TFTs and cerebral cortex of embryos. After depletion of the endogenous TH, Mct8-heterozygous pregnant dams carrying both wild-type (Wt) and Mct8-deficient (Mct8KO) male embryos were given DITPA. Effects were compared with those treated with levothyroxine (L-T4). With DITPA treatment, serum DITPA concentration was not different in the two genotyp...

  • inherited defects in thyroid hormone cell membrane transport and metabolism
    Best Practice & Research Clinical Endocrinology & Metabolism, 2014
    Co-Authors: Alexandra M Dumitrescu
    Abstract:

    The description of two novel human defects in the last ten years has uncovered new aspects of thyroid hormone physiology with regard to cell-membrane transport and intracellular metabolism. Mutations in the X-linked Monocarboxylate Transporter 8 (MCT8) gene result in an invalidating neurodevelopmental phenotype in males and pathognomonic thyroid functions tests with high T3, low rT3, low or low normal T4, and normal or slightly high TSH. Recessive mutations in the selenocysteine insertion sequence binding protein 2 (SBP2) gene present a variable clinical phenotype depending on the severity of the defect and its consequences on the selenoprotein hierarchy. Most characteristic is the thyroid phenotype of low serum T3, high T4, high rT3, and slightly elevated TSH levels. Herein we review all known cases of MCT8 and SBP2 deficiency and describe each disease in terms of the clinical, biochemical, genetic, and therapeutic aspects.

  • inherited defects of thyroid hormone cell membrane transport review of recent findings
    Current Opinion in Endocrinology Diabetes and Obesity, 2013
    Co-Authors: Samuel Refetoff, Alexandra M Dumitrescu
    Abstract:

    PURPOSE OF REVIEW This review summarizes the most significant findings over the last year regarding human and animal models deficient in thyroid hormone cell-membrane Transporters (THCMTs). Although several THCMTs have been modelled in genetically engineered mice, the only THCMT defect known in humans is that caused by mutations in the Monocarboxylate Transporter 8 (MCT8) gene. RECENT FINDINGS The importance of several amino acid residues has been assessed in vitro to further our understanding on the structure-function of the MCT8. The administration of the thyromimetic compound, diiodothyropropionic acid, has been tested in patients with MCT8 gene mutations, following studies of its use in mice. Another thyroid hormone analogue, 3,3',5,5'-tetraiodothyroacetic acid, was tested in Mct8-deficient mice. The phenotypes of L-type aminoacid Transporter 2 and organic anion transporting polypeptide 1C1 deficiencies have been studied in mouse models. Mct8/organic anion transporting polypeptide 1C1 double knockout mice have been shown to manifest neurodevelopmental deficits. Zebrafish is emerging as another vertebrate model that may be useful to study the role of Mct8 in brain development. SUMMARY Studies on the pathogenesis and therapy of MCT8 deficiency are in progress, and new vertebrate models that are suitable to study the neurological consequences of the syndrome are being explored.