scholarly journals Changes in Thyroid Status During Perinatal Development of MCT8-Deficient Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (7) ◽  
pp. 2533-2541 ◽  
Author(s):  
Alfonso Massimiliano Ferrara ◽  
Xiao-Hui Liao ◽  
Pilar Gil-Ibáñez ◽  
Teresa Marcinkowski ◽  
Juan Bernal ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Gene Mutations ◽  
Perinatal Period ◽  
Deficiency Syndrome ◽  
Psychomotor Retardation ◽  
Relative Increase ◽  
Monocarboxylate Transporter ◽  
Adult Mice ◽  
Mct8 Deficiency ◽  
Deficient Mice

Abstract Patients with the monocarboxylate transporter 8 (MCT8) deficiency syndrome present with a severe psychomotor retardation and abnormal serum thyroid hormone (TH) levels, consisting of high T3 and low T4 and rT3. Mice deficient in Mct8 replicate the thyroid phenotype of patients with the MCT8 gene mutations. We analyzed the serum TH levels and action in the cerebral cortex and in the liver during the perinatal period of mice deficient in Mct8 to assess how the thyroid abnormalities of Mct8 deficiency develop and to study the thyroidal status of specific tissues. During perinatal life, the thyroid phenotype of Mct8-deficient mice is different from that of adult mice. They manifest hyperthyroxinemia at embryonic day 18 and postnatal day 0. This perinatal hyperthyroxinemia is accompanied by manifestations of TH excess as evidenced by a relative increase in the expression of genes positively regulated by T3 in both the cerebral cortex and liver. An increased tissue accumulation of T4 and T3 and the expression of TH alternative transporters, including Lat1, Lat2, Oatp1c1, and Oatp3a1 in the cortex and Lat2 and Oatp1b2 in the liver, suggested that Mct8 deficiency either directly interferes with tissue efflux of TH or indirectly activates other transporters to increase TH uptake. This report is the first to identify that the ontogenesis of TH abnormalities in Mct8-deficient mice manifests with TH excess in the perinatal period.

scholarly journals High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase

2015 ◽  
Vol 4 (Suppl. 1) ◽  
pp. 87-91 ◽  
Author(s):  
Eva K. Wirth ◽  
Eddy Rijntjes ◽  
Franziska Meyer ◽  
Josef Köhrle ◽  
Ulrich Schweizer
Keyword(s):  
Thyroid Hormone ◽  
Serum Levels ◽  
Underlying Mechanism ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Type I ◽  
Hormone Levels ◽  
Thyroid Hormone Levels ◽  
Mct8 Deficiency ◽  
Deficient Mice

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.

scholarly journals Consequences of Monocarboxylate Transporter 8 Deficiency for Renal Transport and Metabolism of Thyroid Hormones in Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 802-809 ◽  
Author(s):  
Marija Trajkovic-Arsic ◽  
Theo J. Visser ◽  
Veerle M. Darras ◽  
Edith C. H. Friesema ◽  
Bernhard Schlott ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Psychomotor Retardation ◽  
High Serum ◽  
Monocarboxylate Transporter ◽  
Iodothyronine Deiodinase ◽  
Serum T4 ◽  
Mct8 Deficiency ◽  
Low Serum

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 MCT8 deficiency either directly interferes with the renal efflux of thyroid hormones or activates indirectly other renal thyroid hormone transporters that preferentially mediate the renal uptake of thyroid hormones. Our findings indicate that the enhanced uptake and accumulation of T4 in the kidneys of MCT8 null mice together with the increased renal conversion of T4 into T3 by increased renal deiodinase type 1 activities contributes to the generation of the low-serum T4 and the increase in circulating T3 levels, a hallmark of MCT8 deficiency.

scholarly journals Oligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Min Joung Kim ◽  
Steven Petratos
Keyword(s):  
Thyroid Hormone ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Therapeutic Effects ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Extracellular Transport ◽  
Synaptic Dynamics ◽  
Mct8 Deficiency

Oligodendrocytes are supporting glial cells that ensure the metabolism and homeostasis of neurons with specific synaptic axoglial interactions in the central nervous system. These require key myelinating glial trophic signals important for growth and metabolism. Thyroid hormone (TH) is one such trophic signal that regulates oligodendrocyte maturation, myelination, and oligodendroglial synaptic dynamics via either genomic or nongenomic pathways. The intracellular and extracellular transport of TH is facilitated by a specific transmembrane transporter known as the monocarboxylate transporter 8 (MCT8). Dysfunction of the MCT8 due to mutation, inhibition, or downregulation during brain development leads to inherited hypomyelination, which manifests as psychomotor retardation in the X-linked inherited Allan-Herndon-Dudley syndrome (AHDS). In particular, oligodendroglial-specific MCT8 deficiency may restrict the intracellular T3 availability, culminating in deficient metabolic communication between the oligodendrocytes and the neurons they ensheath, potentially promulgating neurodegenerative adult diseases such as multiple sclerosis (MS). Based on the therapeutic effects exhibited by TH in various preclinical studies, particularly related to its remyelinating potential, TH has now entered the initial stages of a clinical trial to test the therapeutic efficacy in relapsing-remitting MS patients (NCT02506751). However, TH analogs, such as DITPA or Triac, may well serve as future therapeutic options to rescue mature oligodendrocytes and/or promote oligodendrocyte precursor cell differentiation in an environment of MCT8 deficiency within the CNS. This review outlines the therapeutic strategies to overcome the differentiation blockade of oligodendrocyte precursors and maintain mature axoglial interactions in TH-deprived conditions.

scholarly journals Regional Difference in Myelination in Monocarboxylate Transporter 8 Deficiency: Case Reports and Literature Review of Cases in Japan

2021 ◽  
Vol 12 ◽  
Author(s):  
Hideyuki Iwayama ◽  
Tatsushi Tanaka ◽  
Kohei Aoyama ◽  
Masaharu Moroto ◽  
Shinsuke Adachi ◽  
...  
Keyword(s):  
Case Reports ◽  
Internal Capsule ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Imaging Features ◽  
Optic Radiation ◽  
Normal Children ◽  
Posterior Limb ◽  
Mct8 Deficiency ◽  
Delayed Myelination

Background: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transmembrane transporter protein. MCT8 deficiency induces severe X-linked psychomotor retardation. Previous reports have documented delayed myelination in the central white matter (WM) in these patients; however, the regional pattern of myelination has not been fully elucidated. Here, we describe the regional evaluation of myelination in four patients with MCT8 deficiency. We also reviewed the myelination status of previously reported Japanese patients with MCT8 deficiency based on magnetic resonance imaging (MRI).Case Reports: Four patients were genetically diagnosed with MCT8 deficiency at the age of 4–9 months. In infancy, MRI signal of myelination was observed mainly in the cerebellar WM, posterior limb of internal capsule, and the optic radiation. There was progression of myelination with increase in age.Discussion: We identified 36 patients with MCT8 deficiency from 25 families reported from Japan. The available MRI images were obtained at the age of <2 years in 13 patients, between 2 and 4 years in six patients, between 4 and 6 years in three patients, and at ≥6 years in eight patients. Cerebellar WM, posterior limb of internal capsule, and optic radiation showed MRI signal of myelination by the age of 2 years, followed by centrum semiovale and corpus callosum by the age of 4 years. Most regions except for deep anterior WM showed MRI signal of myelination at the age of 6 years.Conclusion: The sequential pattern of myelination in patients with MCT8 deficiency was largely similar to that in normal children; however, delayed myelination of the deep anterior WM was a remarkable finding. Further studies are required to characterize the imaging features of patients with MCT8 deficiency.

scholarly journals The Monocarboxylate Transporter 8 Linked to Human Psychomotor Retardation Is Highly Expressed in Thyroid Hormone-Sensitive Neuron Populations

Endocrinology ◽  
2005 ◽  
Vol 146 (4) ◽  
pp. 1701-1706 ◽  
Author(s):  
Heike Heuer ◽  
Michael K. Maier ◽  
Sandra Iden ◽  
Jens Mittag ◽  
Edith C. H. Friesema ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Thyroid Hormone ◽  
System Development ◽  
Perinatal Period ◽  
Psychomotor Retardation ◽  
Nervous System Development ◽  
Monocarboxylate Transporter ◽  
Target Cells

Abstract Recent genetic analysis in several patients presenting a severe form of X-linked psychomotor retardation combined with abnormal thyroid hormone (TH) levels have revealed mutations or deletions in the gene of the monocarboxylate transporter 8 (MCT8). Because in vitro MCT8 functions as a TH transporter, the complex clinical picture of these patients indicated an important role for MCT8 in TH-dependent processes of brain development. To provide a clue to the cellular function of MCT8 in brain, we studied the expression of MCT8 mRNA in the murine central nervous system by in situ hybridization histochemistry. In addition to the choroid plexus structures, the highest transcript levels were found in neo- and allocortical regions (e.g. olfactory bulb, cerebral cortex, hippocampus, and amygdala), moderate signal intensities in striatum and cerebellum, and low levels in a few neuroendocrine nuclei. Colocalization studies revealed that MCT8 is predominantly expressed in neurons. Together with the spatiotemporal expression pattern of MCT8 during the perinatal period, these results strongly indicate that MCT8 plays an important role for proper central nervous system development by transporting TH into neurons as its main target cells.

scholarly journals MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated With the Absence of a Functional Type 3 Deiodinase

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3266-3277 ◽  
Author(s):  
J. Patrizia Stohn ◽  
M. Elena Martinez ◽  
Kassey Matoin ◽  
Beatriz Morte ◽  
Juan Bernal ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Growth Retardation ◽  
Double Mutant ◽  
Elevated Serum ◽  
Monocarboxylate Transporter ◽  
Central Hypothyroidism ◽  
Newborn Mice ◽  
Adult Mice ◽  
Mct8 Deficiency ◽  
Type 3

Mice deficient in the type 3 deiodinase (D3KO mice) manifest impaired clearance of thyroid hormone (TH), leading to elevated levels of TH action during development. This alteration causes reduced neonatal viability, growth retardation, and central hypothyroidism. Here we examined how these phenotypes are affected by a deficiency in the monocarboxylate transporter 8 (MCT8), which is a major contributor to the transport of the active thyroid hormone, T3, into the cell. MCT8 deficiency eliminated the neonatal lethality of type 3 deiodinase (D3)-deficient mice and significantly ameliorated their growth retardation. Double-mutant newborn mice exhibited similar peripheral thyrotoxicosis and increased brain expression of T3-dependent genes as mice with D3 deficiency only. Later in neonatal life and adulthood, double-mutant mice manifested central and peripheral TH status similar to mice with single MCT8 deficiency, with low serum T4, elevated serum TSH and T3, and decreased T3-dependent gene expression in the hypothalamus. In double-mutant adult mice, both thyroid gland size and the hypothyroidism-induced rise in TSH were greater than those in mice with single D3 deficiency but less than those in mice with MCT8 deficiency alone. Our results demonstrate that the marked phenotypic abnormalities observed in the D3-deficient mouse, including perinatal mortality, growth retardation, and central hypothyroidism in adult animals, require expression of MCT8, confirming the interdependent relationship between the TH transport into cells and the deiodination processes.

scholarly journals Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

2011 ◽  
Vol 25 (1) ◽  
pp. 1-14 ◽  
Author(s):  
W. Edward Visser ◽  
Edith C. H. Friesema ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Psychomotor Retardation ◽  
Cellular Level ◽  
Monocarboxylate Transporter ◽  
Causative Role ◽  
Organic Anion Transporting Polypeptide ◽  
Neurological Abnormalities ◽  
Knockout Animals

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

scholarly journals Effects of DSPP Gene Mutations on Periodontal Tissues

2021 ◽  
Author(s):  
Zhaojun Jing ◽  
Zhibin Chen ◽  
Yong Jiang
Keyword(s):  
Alveolar Bone ◽  
Gene Mutations ◽  
Specific Protein ◽  
Dentinogenesis Imperfecta ◽  
Dentin Sialophosphoprotein ◽  
Periodontal Tissues ◽  
Furcation Involvement ◽  
Almost All ◽  
Alveolar Bone Defect ◽  
Deficient Mice

AbstractDentin sialophosphoprotein (DSPP) gene mutations cause autosomal dominantly inherited diseases. DSPP gene mutations lead to abnormal expression of DSPP, resulting in a series of histological, morphological, and clinical abnormalities. A large number of previous studies demonstrated that DSPP is a dentinal-specific protein, and DSPP gene mutations lead to dentin dysplasia and dentinogenesis imperfecta. Recent studies have found that DSPP is also expressed in bone, periodontal tissues, and salivary glands. DSPP is involved in the formation of the periodontium as well as tooth structures. DSPP deficient mice present furcation involvement, cementum, and alveolar bone defect. We speculate that similar periodontal damage may occur in patients with DSPP mutations. This article reviews the effects of DSPP gene mutations on periodontal status. However, almost all of the research is about animal study, there is no evidence that DSPP mutations cause periodontium defects in patients yet. We need to conduct systematic clinical studies on DSPP mutation families in the future to elucidate the effect of DSPP gene on human periodontium.

Abstract 280: Deficiency of FKBP12 in the Heart Leads to Impaired Contractility and Pregnancy Induced Cardiomyopathy

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Joshua Oakes ◽  
Susan Hamilton
Keyword(s):  
Ejection Fraction ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Heart Weight ◽  
Mild Phenotype ◽  
Adult Mice ◽  
Significant Difference ◽  
Fk506 Binding Proteins ◽  
Deficient Mice ◽  
Fractional Shortening

FK506 Binding Proteins (FKBPs) are a family of cis-trans prolyl isomerases that bind rapamycin and FK506. FKBP12 and 12.6 interact with ryanodine receptors (RyR), homotetrameric transmembrane ion channels that regulate Ca2+ release from the sarcoplasmic reticulum (SR). FKBP12 interacts with RyR1 in skeletal muscle and FKBP12.6 interacts with RyR2 in cardiac muscle to regulate the Ca2+ leak properties of these channels. Recently it has been suggested that FKBP12 also plays a role in regulating RyR2 activity. Using mice with a cardiac specific deficiency in FKBP12, we analyzed the role of FKBP12 in cardiac function. We found that both male and female mice with a α-MyHC Cre/Lox mediated deficiency in FKBP12 in the heart (FKBP12 KD) developed a mild dilated cardiomyopathy, with enlarged left ventricular diameter both during systole and diastole, decreased ejection fraction and decreased fractional shortening. To elucidate the mechanism for these effects we assessed Ca2+ sparks in isolated cardiomyocytes. We found an increase in both Ca2+ spark frequency and spark amplitude in FKBP12 cardiac deficient mice without a change in spark duration. Despite a mild phenotype in adult mice, we found that approximately 25% of all pregnancies (26/106) in the FKBP12 deficient mice resulted in the mothers dying following the birth. Autopsies show that these cardiac specific FKBP12 deficient mice had increased heart weight and significantly dilated ventricles compared to female Cre mice. Our data suggest that a cardiac specific deficiency in FKBP12 leads to the development of pregnancy induced cardiomyopathy. Echocardiography on FKBP12 deficient mice one day after giving birth found that there was no significant difference in ejection fraction or fractional shortening compared to α-MyHC Cre control mice. FKBP12 deficient females, however, had larger hearts and 50% (2/4) displayed heart failure and died. In conclusion, we show that FKBP12 does indeed alter Ca2+ handling in the heart and that a loss of FKBP12 leads to the development of pregnancy induced cardiomyopathies in females.

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